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Chlorella supplement health benefit and side effects, review of medical uses and influence on immune system by Ray Sahelian, M.D.
December 28 2016
Chlorella is a green algae that grows in fresh water. It emerged over 2 billion years ago, and was the first form of a plant with a well-defined nucleus. Each Chlorella microorganism is composed of a nucleus, starch grains, chloroplasts and mitochondria surrounded by a cell wall composed mainly of cellulose. Because it is a microscopic organism, it was not discovered until the late 19th century, deriving its name from the Greek, “chloros” meaning green and “ella” meaning small. There are various species. Although the algae grow naturally in fresh water, chlorella destined for human consumption is generally cultivated in large, fresh mineral water pools under direct sunlight. It is a tiny, unicellular green algae, three to eight micrometres in diameter, which when grown in large quantities gives lakes and rivers a green tint.
Although it was discovered by a Dutch microbiologist in 1890 and studied as a potential protein source by German scientists, it wasn’t until after the Second World War that the reality of food shortages, combined with the expectation of a population boom, led to bureaucrats globally examining chlorella in the hope that it could be used to feed the masses cheaply – this proved uneconomic. Later, NASA studied it with the possibility of feeding it to astronauts. It is currently being used in some countries to help cancer patients.
What does the research say about the benefits?
I could only find a few studies with chlorella involving humans. Based on very early research, it appears that it may play a role in fibromyalgia, hypertension, or ulcerative colitis and has an effect on the immune system. We definitely need a few more studies to confirm initial findings.
Q. What is the difference between chlorella broken cell and the unbroken cell version?
A. The outer cell wall of chlorella has a low digestibility, which requires an opening to digest its nutrients. A variety of methods are used by different makers to break down the cell wall to enhance its digestibility. The broken cell version will have a higher absorption rate than the unbroken cell.
Helps improve overall health
Japanese researchers claim that this green algae could reduce body-fat percentage and blood-glucose levels and help those who have type 2 diabetes, obesity, cancer patients or those with heart disease. This supplement could boost energy and improve mood. Some claim that chlorella stimulates the growth of probiotic or friendly bacteria, and its cell walls absorb toxins within the intestine and encourage peristalsis. Randall Merchant, professor of Neurosurgery and Anatomy at Virginia Commonwealth University, in the US, researches brain tumors, traumatic brain injury, and stroke. In 1986, he began clinical trials, funded by chlorella producer Sun Chlorella ‘A’, into whether the algae might improve a patient’s immune system. “Fascinating,” is how he describes the results. “It didn’t make brain tumours go away or shrink, so it didn’t cure the cancer, but it did help the patients by boosting their immune system so that they resisted opportunistic infections.” Since then, Prof Merchant has performed clinical trials to test whether chlorella could be useful in helping with chronic conditions such as fibromyalgia, ulcerative colitis and hypertension. In the first two trials, his team found that “patients’ symptoms diminished quite nicely”. For hypertension, the results were more dramatic; while it lowered blood pressure in about 50 per cent of cases, which was promising, the studies showed that it also significantly lowered serum cholesterol. In 2008, he examined the effects chlorella has on those with metabolic syndrome – the collection of symptoms that often lead to the cells in our bodies becoming less sensitive to insulin, and therefore a precursor to diabetes. Chlorella turns on the genes that control the way insulin is normally used by the cells in the body and may be of benefit to those with metabolic syndrome.
Antioxidant benefit and eye health
Consumption increases levels of antioxidants in the bloodstream.
Antioxidant and anti-cataract effects of Chlorella on rats with streptozotocin-induced diabetes.
J Nutr Sci Vitaminol 2003.
A 7% Chlorella powder was fed to rats with streptozotocin-induced diabetes for 11 weeks. At the end of the experiment, chlorella had decreased the blood glycated hemoglobin (hemoglobin A1c) and serum cholesterol levels significantly, however, it had not affected the serum glucose concentration. The serum lipid peroxide value (TBARS value) in the rats fed chlorella was lower than that of the control rats. In the liver and kidney, Chlorella also reduced chemiluminescent intensities. In addition, it delayed the development of lens opacities. These results indicate that chlorella has antioxidant activity and may be beneficial for the prevention of diabetic complications such as cataracts.
Attenuating effect of chlorella supplementation on oxidative stress and NFkappaB activation in peritoneal macrophages and liver of C57BL/6 mice fed on an atherogenic diet.
Biosci Biotechnol Biochem. 2003.
Our results suggest that chlorella supplementation may attenuate oxidative stress by reducing reactive oxygen production and increasing antioxidative processes, thus suppressing inflammatory mediator activation in peritoneal macrophages and liver.
Nutr J. 2014. Impact of daily Chlorella consumption on serum lipid and carotenoid profiles in mildly hypercholesterolemic adults: a double-blinded, randomized, placebo-controlled study. Eligible subjects (n = 63) were randomized to either Chlorella (5 g/day) or placebo for a double-blinded trial with a 2-week lead-in period and a 4-week intervention period. Serum triglycerides, total cholesterol, lipoproteins, apolipoproteins and carotenoids were assessed at the beginning and the end of the trial. Daily consumption of Chlorella supplements provided the potential of health benefits reducing serum lipid risk factors, mainly triglycerides and total cholesterol, in mildly hypercholesterolemic subjects.
Nutritional supplementation with Chlorella pyrenoidosa for patients with fibromyalgia syndrome: a pilot study.
Phytother Res. 2000.
The objective of the present study was to determine if adding nutritional supplements derived from the unicellular green alga, Chlorella pyrenoidosa, produced any improvements in the clinical and functional status in patients with moderately severe symptoms of fibromyalgia syndrome. Each day for 2 months, participants consumed two commercially available products, 10 g of ‘Sun Chlorella’ tablets and 100 mL of liquid ‘Wakasa Gold’. There was a 22% decrease in pain intensity. Blood samples taken on each occasion indicated no significant alterations in serum chemistries, formed elements, and circulating lymphocyte subsets. Seven patients felt that the dietary supplement had improved their fibromyalgia symptoms, while six thought they had experienced no change, and five believed the symptoms had worsened over the time of the trial. The results of this pilot study suggest that dietary Chlorella supplementation may help relieve the symptoms of fibromyalgia in some patients and that a larger, more comprehensive double-blind, placebo-controlled clinical trial in these patients is warranted.
Clin Lab. 2013. Investigation of the effects of Chlorella vulgaris supplementation on the modulation of oxidative stress in apparently healthy smokers. Supplementation with C. vulgaris extract significantly improves antioxidant status and attenuates lipid peroxidation in chronic cigarette smokers. Hence, C. vulgaris might prevent the disease burden and mortality rate associated with smoking.
Chlorella testimonial received by email
I was just reading your article on Chlorella and I felt you may be interested in hearing that while you do make mention that chlorella may contribute in improving energy and mood in general, I feel that the overall tone of that mention in your article does not match the true potential this product. I’ve only been taking it for about a month and I can tell you no anti-depressants ever worked anywhere near as good as chlorella for me. Not that I was taking it for that purpose mind you, but luck helping I found something nice.
Chlorella side effects, safety, risk, toxicity, nausea appears to be common
Although no significant chlorella side effects have been reported in the medical literature, we have had several reports of gastrointestinal side effects with the use of such supplements. These chlorella side effects involved nausea and vomiting and I have listed some of the emails we have received.
I started taking chlorella about three weeks ago. I am a Yoga teacher and consider myself very healthy. However, on the third day I was sick after taking Chlorella. The next three days i felt fine, in fact great and then I started tobe sick again over the next 5 days. The last day was particularly bad, I was unable to hold down water and spent the day in the toilet. I stopped using it for another 6 days and felt fine. So I tried again with a very small dose.Within an hour and a half I became so sick with chronic diarrhoea and severe vomiting that I collapsed and was taken to hospital. This is the third day I am in bed feeling awful. I have never experienced anything like this in my life-noteven dysentery was this bad. Surely it should come with a warning. I have looked up many forums on the subject and find that I am far from the only person who has suffered.
October 2014 – I read your article on chlorella and the feedback of so many that experienced the same as I do with the power vomiting, more severe than when a stomach virus! Has anyone figured out why this occurs? I have had people tell me just to not take it, which I don’t as just a mouthful of a mixture of herbs, greens including the tiniest amount of chlorella makes me vomit for hours, others have said to take cellulase enzymes with it, which I’ve found hasn’t worked either. It would be great to find out why it has this reaction, hoping you can help clarify why.
A. I really do not know why this adverse effect occurs.
February 2014 – I started taking chlorella by Source Naturals Yaeyama about two weeks ago and yesterday experienced violent vomiting. It took 24 hours to recover. Since this seems to be a common experience, I won’t be trying it again.
I started taking a chlorella supplement several weeks ago. I did not take them everyday. Last Monday I took Chlorella about an hour after I ate lunch. Within 3 hours I had an upset stomach and threw up several time that night. The next day I was alright. I did not take chlorella for the rest of the week due to I thought that it may have something to do with my sickness. Yesterday, a week later I decided to try chlorella again. This time I took it right after I ate. within in three hours I was violently sick. I was throwing up every 2 to three seconds. It was so bad I got dehydrated within an hour and was so disoriented that an ambulance had to pick me up to take me to the Hospital, By this time the Paramedics said I was throwing up a lot of bile. The doctors at the emergency room told me that it was more likely a reaction to the chlorella. Has anyone else had these kind of side affects? I do not even take the complete recommended dosage. What could have caused such a reaction. I have had stomach viruses before. This was the worst thing that I have ever had. I thought I was dying. How can something that is suppose to be good for you cause such a reaction? The brand is Source Naturals Yaeyama Chlorella. It had just vitamins in it and mixed carotenoids.
I tried it on two different occasions and vomited for a least an hour after taking the chlorella supplements. I thought that I was the only one who had this experience because I hadn’t seen any comment or questions like this before concerning chlorella pills. I’m quite sure there are several other people who have had this experience with chlorella pills.
This is the second report we have had regarding vomiting side effect after taking chlorella supplements.
I took it in powder form for about 2 weeks. It seemed to agree with me then one day I took it and within one hour I was experiencing the worst case of what felt like food poisoning you can ever imagine. Severe vomiting and diarrhea for several hours. I waited about a week to try again( not believing it could possibly be this wonderful food supplement that I was so impressed by initially) and sure enough the same thing happened. Still, I was undaunted and a week later I tried again but this time I took only 1/8th of a dose. Within one hour once again I was vomiting and the day was ruined due to the fatigue of just getting it out of my system. I am stymied by this and now I’m concerned about what might be causing me to reject it. I have no known diseases or conditions. The chlorella product I took is reputable (Sequel) and has been stored properly.
I just wanted to add my two cents to the issue of immediate sickness and side effect after taking chlorella supplement. I was reading your chlorella supplement questions site, and noted a couple of people had been violently ill when taking it. This has also happened to me, more than once first when taking a chlorella supplement prescribed by my naturopath and then yesterday) when unknowingly drinking a fruit smoothie that contained chlorella. The sickness was debilitating vomiting, diarrhea, etc. and left me on the bathroom floor for four hours. Someone should do chlorella studies on this effect, as it appears I’m not the only one.
In the past I was able to take it with no problem (NOW chlorella powder). But when I tried it a few weeks later, I vomited all day and was very, very sick. Then I tried it again about a week later and the same thing happened. I don’t know if I became allergic to it, or what, but I won’t take any type of chlorella now.
I just want to report vomiting violently several hours after taking chlorella supplements – this happened two times and I will never use it again. As in one of the comments on your site an ambulance was called one time. In my experience the chlorella applies itself systemically – I felt sensations from the head to the feet. It also moves one into an altered state of consciousness, the kind of state one enters any time one is quite ill. The brand I used was BioPure. I had another brand a while back and never had any problem with it.
I am witting you to report to you how very ill I became after taking chlorella supplement. The first time I took it the response was delayed (24-48 hours, after I first started). The next time, I tried it, it was only a matter of 4 hours or so, before I was violently vomiting. It took about 24 hours to recover, each time.
I have experienced gastrointestinal upset. I have tend to have a sensitive bowel, but thought that chlorella was beneficial for this. Also I suffer from fibromyalgia and migraine. I had tried a year ago New Chapter Chlorella on one occasion and do not recall having any problems. However, when I bought and took two tablets of brand called Organika I got sick on two occasions. The first time I got severe nausea and flu like symptoms within a few hours of taking two tablets. Miraculously, drinking ginger tea cleared up the symptoms quite quickly. I tried the Organika Chlorella a week later just in case it wasn’t the supplement that had made ill. Again within a few hours, I wasn’t nauseous, but I had severe cramps and then diarrhea, which fortunately was short lived. (email received March 2009)
I started taking chlorella and got a really stuffed nose. I suspected it was the chlorella, and as soon as I stopped taking it I could breathe again! Thought you might want to add this to your side effects testimonials.
I started taking Chlorella for the first time about 5 weeks ago, Kyoto brand. I’ve been taking several supplements over the past few years for my inflammatory bowel disease-like symptoms that have helped me a lot. I started with just 1 three times per day and over the first few weeks gradually increased it to 5 tablets 3 times per day, with 15 tablets containing 3 g of chlorella. I felt great the first few weeks, had better improvement in my symptoms than anything I tried before, but then started having uncontrolled racing thoughts involving past memories, trouble concentrating, irritability and a hyper feeling. The end of last week I started having watery diarrhea, loose stools, stomach cramping, mild headache, trouble sleeping and a panicky feeling that may have been stress from all this. I had slight nausea and chills, but no vomiting. It was getting harder to eat. I was getting fatigued from not eating and sleeping. I don’t take prescription drugs, only the natural supplements I’ve been taking a long time. I researched and found on your website and a few others that it can cause the GI symptoms with some people. I don’t know about the mental symptoms, but they came together and never happened before. I noticed the dose you recommend is much smaller than what I have been taking, so I am going to stop it for a few days, then start very slowly up to the small dose I was taking before these symptoms started. I would like to keep taking it if I can for the benefits. I’m not putting down supplements, I’ve taken them for years with great success, but I don’t agree with some who say that because it’s a natural food supplement it can only have positive effects and no bad side effects. There are many substances found in nature that can have both positive and negative effects on us and vary with different people. (email received October 2011). All of my symptoms were completely gone by the second day after stopping and haven’t returned.
After taking it for about 2 weeks without any ill effects, I started having the following symptoms: diarrhea, extreme thirstiness, and mild vertigo. I did some internet research yesterday and discovered similar symptoms being talked about on your website. I read on another site that impurities in the chlorella (from how it’s grown and manufactured) could cause problems. I also understand that there are elements of the organism itself that could cause problems – the LPS that is part of the cell wall of chlorella may trigger immune system responses that lead to systemic inflammations.
I am not aware of studies that have reviewed this supplement in terms of its safety during pregnancy.
Chlorella Research study
Effects of chlorella on activities of protein tyrosine phosphatases, matrix metalloproteinases, caspases, cytokine release, B and T cell proliferations, and phorbol ester receptor binding.
J Med Food. 2004.
A Chlorella powder was screened using 52 in vitro assay systems for enzyme activity, receptor binding, cellular cytokine release, and B and T cell proliferation. The screening revealed a very potent inhibition of human protein tyrosine phosphatase activity of CD45 and PTP1C. Other inhibitory activities and their IC(50) values included inhibition of the human matrix metalloproteinases and the human peptidase caspases, as well as release of the cytokines interleukin (IL)-1, IL-2, IL-4, IL-6, interferon-gamma, and tumor necrosis factor-alpha from human peripheral blood mononuclear cells. Chlorella also inhibited B cell proliferation in mouse splenocytes and T cell proliferation in mouse thymocytes. These results reveal potential pharmacological activities that, if confirmed by in vivo studies, might be exploited for the prevention or treatment of several serious pathologies, including inflammatory disease and cancer.
A hot water extract of Chlorella pyrenoidosa reduces body weight and serum lipids in ovariectomized rats.
Phytother Res. 2004.
The effects of a hot water extract of Chlorella pyrenoidosa, which contains chlorella growth factor, on the body weight, serum lipids, and the bone mass were evaluated using an ovariectomized rat as a model for postmenopausal bone loss. Rats were divided into four groups: sham-operated (Sham), Sham given the chlorella growth factor solution, ovariectomized (OVX), and OVX given the chlorella growth factor solution, respectively. Administration of the extract to OVX rats suppressed the body weight gain. After 7 weeks, the administration of the extract to the OVX group reduced increases in both serum total cholesterols and high-density lipoprotein (HDL) cholesterols. It also normalized the decrease of triglyceride level in the OVX group. The ovariectomy decreased the tibial bone mineral density (BMD) by 19%, and the administration of the extract to OVX rats did not inhibit this decrease. These results suggest that a dietary supplement of chlorella growth factor may be useful to control the body weight and improve lipid metabolism of menopausal women.
I am currently a student at Great Neck South High School in New York. I have read your site about the health benefits and was wondering if you knew where I could buy the algae Chlorella pyrenoidosa. I need this to do an experiment on whether it really does have hypoglycemic properties.
It appears that Sun Chlorella brand has this particular genus. You can google Sun Chlorella and find an online store that sells it.
Accumulation of astaxanthin and lutein in Chlorella zofingiensis (Chlorophyta).
Appl Microbiol Biotechnol. 2004.
When grown photoautotrophically, Chlorella zofingiensis strain CCAP 211/14 accumulates a significant amount of valuable carotenoids, namely astaxanthin and lutein, of increasing demand for use as feed additives in fish and poultry farming, as colorants in food, and in health care products.
Safety and immunoenhancing effect of a Chlorella-derived dietary supplement in healthy adults undergoing influenza vaccination: randomized, double-blind, placebo-controlled trial.
We evaluated the effect of an oral dietary supplement derived from the edible microalga Chlorella pyrenoidosa on immune response after influenza vaccination. We conducted a randomized, double-blind, placebo-controlled community-based clinical trial in a convenience sample of 124 healthy adults at least 50 years of age randomly assigned to receive the study product (200 or 400 mg of a Chlorella-derived dietary supplement) or placebo. Participants took the study product or placebo once daily for 28 days. On day 21, we administered a single dose of a licensed trivalent, inactivated influenza vaccine. We obtained serum specimens to measure hemagglutination inhibition titres before and 7 and 21 days after vaccination. The primary immunological outcomes were the proportion of participants with a 4-fold or greater increase in antibodies and geometric mean antibody titres after vaccination.There were no differences in the proportions of recipients of 200 or 400 mg of the Chlorella -derived dietary supplement or placebo who achieved at least a 4-fold increase in antibodies (proportions for the 3 virus strains ranged from 17% to 28% for the 200-mg group, from 11% to 22% for the 400-mg group and from 19% to 21% for the placebo group. Reports of adverse events were similar for recipients of the supplement and placebo, except with regard to fatigue, which was reported more frequently by recipients of 200 mg of the supplement (18/41 or 44%) than by those who received 400 mg of the supplement or placebo. Recipients of 400 mg of the chlorella supplement who were 55 years of age or younger had significantly higher geometric mean antibody titres against influenza A/New Caledonia 21 days after vaccination and against B/Yamanashi 7 days after vaccination; the trends were nonsignificant for titres against A/Panama. We also observed similar increases for the proportions of subjects with a 2-fold or greater or a 4-fold or greater increase in antibodies. The Chlorella derived dietary supplement did not have any effect in increasing the antibody response to influenza vaccine in the overall study population, although there was an increase in antibody response among participants aged 50-55 years. Adverse events were similar among those receiving the supplement and the placebo.
A review of recent clinical trials of the nutritional supplement Chlorella pyrenoidosa in the treatment of fibromyalgia, hypertension, and ulcerative colitis.
Altern Ther Health Med. 2001.
It has been suggested that the consumption of natural “whole foods” rich in macronutrients has many healthful benefits for those who otherwise ingest a normal, nonvegetarian diet. One example is dietary supplements derived from Chlorella pyrenoidosa, a unicellular fresh water green alga rich in proteins, vitamins, and minerals. To find evidence of the potential of chlorella dietary supplements to relieve signs and symptoms, improve quality of life, and normalize body functions in people with chronic illnesses, specifically fibromyalgia, hypertension, and ulcerative colitis. Fifty-five subjects with fibromyalgia, 33 with hypertension, and 9 with ulcerative colitis. Subjects consumed 10 g of pure chlorella in tablet form and 100 mL of a liquid containing an extract of chlorella each day for 2 or 3 months. For fibromyalgia patients, assessments of pain and overall quality of life. For hypertensive patients, measurements of sitting diastolic blood pressure and serum lipid levels. For patients with ulcerative colitis, determination of state of disease using the Disease Activity Index. Daily dietary supplementation with chlorella may reduce high blood pressure, lower serum cholesterol levels, accelerate wound healing, and enhance immune functions. The potential of chlorella to relieve symptoms, improve quality of life, and normalize body functions in patients with fibromyalgia, hypertension, or ulcerative colitis suggests that larger, more comprehensive clinical trials of chlorella are warranted.
There are various chlorella products on the market, including Sun Chlorella. I am not familiar with the different brands of chlorella and thus do not know if Sun Chlorella is better than other brands.
Q. I read somewhere that chlorella removes toxins from the body. Is that true? Also, I read that one needs to check their blood iron level before taking chlorella.
A. When people talk in such vague terms as ‘toxins,’ it makes me think that either they do not understand the complexity of the human body, or they are just scammers, trying to hype their product. I have not seen any human studies where chlorella was found to remove ‘toxins’ from the body. How are these ‘toxins’ defined, anyway? It makes no sense to me that one has to check their iron level before taking chlorella. It’s like saying one has to check their iron level before eating meat products. There are several milligrams of iron in a few ounces of meat. Three capsules of chlorella will have less than one mg of iron.
Q. Dear Dr. Sahelian: Since you are a respected authority whose input and knowledge I respect, I wanted to ask: In your opinion, does chlorella have any value as a memory enhancement supplement? The flyer from Sun Chlorella claims that a study where seniors took10 a day of their Sun Chlorella pills, in addition to the liquid extract, proved that it has memory enhancing properties. Have you had any experience with Sun Chlorella? I think its probably a pretty good detoxifier. But I’ve never heard you mention it. I love the products you formulate and have just finished reading your Mind Boosters book. Thank you for your time.
A. We have searched Medline and could not find studies with Sun Chlorella and memory. Even if there were one study that showed some benefit, it would pale in comparison to the many studies done with other brain nutrients that are discussed in the Mind Boosters book. Chlorella, in moderation, appears to be a healthy addition to one’s diet and supplement intake, however it is one of countless other beneficial supplements that are available.
I am a healthy 19 year old who participates in sports including lacrosse and kung fu. I have recently been introduced to the health benefits of chlorella and spirulina, but I’m on a student’s budget (one who’s putting himself through a big university) and even though I’d like to take both, I have to choose. I was just wondering if there are certain reasons why I should take one over the other (spirulina versus chlorella).
I am a believer in ingesting a variety of supplements rather than the same one(s) all the time. As such it may be a good idea to take spirulina first, once the bottle is finished to take a week off, and then take a chlorella supplement. It is a good idea to take breaks in between.
I read your post on the chlorella page some saying they got sick. I have been taking chlorella for years along with my wife, my two brothers, their wives, my parents and at least 20 friends and acquaintances. No body I know has ever been sick. Since chlorella and spirulina are a food, not supplements, (there is nothing added to pure chlorella and spirulina), that’s like trying to say I vomit violently from eating green beans. I know that the drug cartels (prescription drugs that is) go to great lengths to suppress anything like chlorella and spirulina as many people find it does make them very healthy. Speaking for myself and all the people I know, it does make a huge difference in our life and health. Now I did do quite a bit of research on chlorella and did find that there are good manufactures and ones you really should stay away from because of contaminates in their product. My wife suffers from migraines. After taking chlorella and spurulina (10 grams a day each) she had not suffered a disabling migraine (it used to happen at least once a month). Now she may get headaches but they are handled with Tylenol and such. Coincidence? Maybe but I think not. She stopped taking this stuff for about a month and suffered a disabling migraine for the firs time in two years. I told her to get back into the routine and she has been fine since. Anyway, I took the time to write this because I really have seen the benefits of chlorella and spurulina.
I have about a tablespoon of chlorella powder everyday. I had previously read that it’s a “food” and that you can’t eat too much. Now I’ve seen warnings on another health website that over-use of chlorella can lead to excessively high iron levels.
As with most supplements, it is a good idea to take breaks from use.
I was reading your section on chlorella and saw the abundance of reader comments on several reactions after ingesting chlorella. I also noticed the absence in your comments and research citations of the profound role of chlorella in heavy metal chelation. Chlorella is an essential oral chelator. There is much research on this. It would be a great service to readers if this could be addressed on your site and research could be posted. I think that the reactions people were experiencing have to do with the heavy metal toxic burden being mobilized and reabsorbed or redistribution. I personally experienced a difficult reaction to chlorella – similar to what other readers described – when taking it for heavy metal chelation. I have read that higher doses should be taken in such cases, as more chlorella is needed to sufficiently bind to the metals it mobilizes.
I have not seen human studies regarding the role of this supplement in terms of chelating heavy metals. Some people think such reactions are due to chelation, but that may not necessarily be so. I question the wisdom of taking more in such cases of getting these unpleasant reactions or side effects.
Q. I’ve read online that Chlorella is a “superfood” that can help children grow taller. Is there any merit to that claim? Also, is Chlorella safe for toddlers – one year old? If so, any particular brands or dosage you recommend?
A. I am not aware of any studies that show it to help kids grow taller and I have not seen safety studies for its use in infants or small children.
Chlorella pyrenoidosa, one of the oldest foods on the planet, is a single-celled plant that grows in fresh water and is about the same size as a human blood cell. It is a green algae, drawing its color from an unusually high amount of chlorophyll (more than any other known plant!). It is grown commercially on water farms, where pure water, clean air, and bright sunlight encourage growth, and special centrifuge equipment is used for harvest. It multiplies quickly, with a complete reproductive cycle every 20 hours.
Purchase Chlorella supplement, 500 mg or 1,000 mg per pill
Chlorella is a green single-celled microalgae that contains very high concentrations of chlorophyll. Before being used as a supplement, it must be gathered, dried to a paste, crushed to a fine emerald green powder, and converted to tiny, soft, crumbly tablets, which smell vaguely of the sea. It supplies high levels of beta carotene, vitamin B-12, Iron, RNA, DNA and Protein.
Genome structure and metabolic features in the red seaweed Chondrus crispus shed light on evolution of the Archaeplastida
- Jonas Colléna,b,1,
- Betina Porcelc,d,e,
- Wilfrid Carréf,
- Steven G. Ballg,
- Cristian Chaparroh,
- Thierry Tonona,b,
- Tristan Barbeyrona,b,
- Gurvan Michela,b,
- Benjamin Noelc,
- Klaus Valentini,
- Marek Eliasj,
- François Artiguenavec,d,e,
- Alok Aruna,b,
- Jean-Marc Auryc,
- José F. Barbosa-Netoh,
- John H. Bothwellk,l,
- François-Yves Bougetm,n,
- Loraine Brilletf,
- Francisco Cabello-Hurtadoo,
- Salvador Capella-Gutiérrezp,q,
- Bénédicte Charriera,b,
- Lionel Cladièrea,b,
- J. Mark Cocka,b,
- Susana M. Coelhoa,b,
- Christophe Colleonig,
- Mirjam Czjzeka,b,
- Corinne Da Silvac,
- Ludovic Delagea,b,
- France Denoeudc,d,e,
- Philippe Deschampsg,
- Simon M. Dittamia,b,r,
- Toni Gabaldónp,q,
- Claire M. M. Gachons,
- Agnès Groisilliera,b,
- Cécile Hervéa,b,
- Kamel Jabbaric,d,e,
- Michael Katinkac,d,e,
- Bernard Kloarega,b,
- Nathalie Kowalczyka,b,
- Karine Labadiec,
- Catherine Leblanca,b,
- Pascal J. Lopezt,
- Deirdre H. McLachlank,l,
- Laurence Meslet-Cladierea,b,
- Ahmed Moustafau,v,
- Zofia Nehra,b,
- Pi Nyvall Colléna,b,
- Olivier Panaudh,
- Frédéric Partenskya,w,
- Julie Poulainc,
- Stefan A. Rensingx,y,z,aa,
- Sylvie Rousvoala,b,
- Gaelle Samsonc,
- Aikaterini Symeonidiy,aa,
- Jean Weissenbachc,d,e,
- Antonios Zambounisbb,s,
- Patrick Winckerc,d,e, and
- Catherine Boyena,b
Edited by Robert Haselkorn, University of Chicago, Chicago, IL, and approved February 6, 2013 (received for review December 18, 2012)
Red seaweeds are key components of coastal ecosystems and are economically important as food and as a source of gelling agents, but their genes and genomes have received little attention. Here we report the sequencing of the 105-Mbp genome of the florideophyte Chondrus crispus (Irish moss) and the annotation of the 9,606 genes. The genome features an unusual structure characterized by gene-dense regions surrounded by repeat-rich regions dominated by transposable elements. Despite its fairly large size, this genome shows features typical of compact genomes, e.g., on average only 0.3 introns per gene, short introns, low median distance between genes, small gene families, and no indication of large-scale genome duplication. The genome also gives insights into the metabolism of marine red algae and adaptations to the marine environment, including genes related to halogen metabolism, oxylipins, and multicellularity (microRNA processing and transcription factors). Particularly interesting are features related to carbohydrate metabolism, which include a minimalistic gene set for starch biosynthesis, the presence of cellulose synthases acquired before the primary endosymbiosis showing the polyphyly of cellulose synthesis in Archaeplastida, and cellulases absent in terrestrial plants as well as the occurrence of a mannosylglycerate synthase potentially originating from a marine bacterium. To explain the observations on genome structure and gene content, we propose an evolutionary scenario involving an ancestral red alga that was driven by early ecological forces to lose genes, introns, and intergenetic DNA; this loss was followed by an expansion of genome size as a consequence of activity of transposable elements.
The red algae, together with the glaucophytes and the Chloroplastida, are members of the Archaeplastida, the phylogenetic group formed during the primary endosymbiosis event that gave rise to the first photosynthetic eukaryote. Red algal genomes, both plastid and nuclear, also contributed, via secondary endosymbiosis, to several other eukaryotic lineages, including stramenopiles, alveolates, cryptophytes, and haptophytes (1), and thus genes of red algal origin are spread widely among the eukaryotes. Knowledge about red algal genes and genomes therefore is crucial for understanding eukaryote evolution. The red macroalgal fossil record stretches back 1.2 billion years, providing the oldest evidence of morphologically advanced, multicellular, sexually reproducing eukaryotes (2). Ecologically, red algae represent the most species-rich group of marine macrophytes with more than 6,000 described species (www.algaebase.org). They are important components of many marine ecosystems, including rocky intertidal shores and coral reefs, and also are present in fresh water (3). Red algae also show some unusual physiological traits. Their photosynthetic antennae are built with phycobiliproteins, the thylakoids are unstacked, and they totally lack flagella and centrioles. In contrast to Chloroplastida, which produce starch in their chloroplasts, red algae store carbon as starch granules in their cytosol (floridean starch) (3). Their cell wall is a complex assemblage of cellulose, various hemicelluloses, and unique sulfated galactans (agars and carrageenans) (4). Economically, red macroalgae are important for their polysaccharide content. For example, carrageenans, the main sulfate-containing compounds in many red algae, are used as texturing agents and had a market value of more than US$500 million in 2010 (5). Red algae, especially nori (Pyropia and Porphyra species), also are used directly for human consumption with a market value of ∼US$1,300 million/y (6).
A number of transcriptomic studies are available on red algae, including the genera Porphyra, Chondrus, and Gracilaria (see ref. 7 and references therein), which investigate developmental processes and physiological responses and establish the contribution of red algae to diverse evolutionary lineages via secondary endosymbiosis events. However, red macroalgae have been the last group of complex multicellular organisms lacking a high-quality reference genome sequence. The closest fully sequenced relative of the red macroalgae is the unicellular extremophile Cyanidioschyzon merolae, which has a reduced genome (8) and belongs to the Cyanidiales, a group that diverged from other red algae about 1.4 billion years ago (1).
In the present study, we analyze the genome of Chondrus crispus Stackhouse (Gigartinales), or Irish moss, an intertidal red seaweed, up to 20 cm long, found on rock shores in the northern Atlantic Ocean. Chondrus is a member of the florideophytes, the largest group of extant red algae, representing 95% of known species (3). It is a common seaweed with a typical red algal triphasic life history with easy access to all three life cycle phases: the haploid female and male gametophytes, the diploid tetrasporophyte, and the diploid carposporophyte (present on the female gametophyte). The cell wall contains carrageenan, typically with ι- and κ-carrageenan in the gametophyte and λ-carrageenan in the sporophyte. In contrast to most other red algae, important scientific background knowledge exists for Chondrus, including studies on the mitochondrial genome (9), transcriptomics (10, 11), interactions with pathogens (12), effects of UV radiation (13), stress metabolism (14), and population ecology (15, 16). Thus, the availability of the C. crispus genome should help promote this organism as a model species for florideophyte algae and shed light on key aspects of eukaryotic evolution.
Results and Discussion
Reduced Genome with Exceptionally Compact Clustered Genes.
The genome sequence was obtained using DNA purified from a clonally growing unialgal culture of a gametophyte of Chondrus crispusand was sequenced using the Sanger technology. The assembled nuclear genome of Chondrus contains 1,266 scaffolds totaling 105 Mbp. A combination of expert and automatic annotation predicts 9,606 genes. The results of the annotation are described in detail in the SI Appendix. Genes are remarkably compact, containing only 1.32 exons on average (i.e., many fewer than other organisms of similar genome size), and most genes (88%) are monoexonic (Fig. 1A). The sparse introns are small, with an average length of 182 nucleotides (Table 1). The intron content of Chondrus and its distant relative C. merolae, as well as the limited data available on the gene structure of other red algae (17), suggest that compact genes are typical for this group and thus possibly are an ancestral trait. It is worth noting that the nucleomorphs of red algal origin in cryptomonads also have low intron content (18). Although we cannot exclude the possibility that a massive loss of introns could have occurred after the secondary endosymbiotic event, this observation suggests that the ancestral endosymbiotic red alga, which gave rise to these nucleomorphs, also had few introns. There is increasing evidence that the last eukaryotic common ancestor was intron rich and that there have been both intron losses and intron gains in the evolution of eukaryotes (19). The low number of introns in red algae thus would be a secondary feature that arose after the split between the green and red lineages about 1.5 billion years ago (1). The few introns that are present in Chondrus possibly have a regulatory function because, on average, transcripts for intron-containing genes accumulated to higher levels than those of monoexonic genes (SI Appendix, Fig. S1.1B). This result is in line with previous observations in other eukaryotes (20, 21).
Genes in Chondrus are clustered in gene-dense regions interspersed with sequences containing numerous repetitive elements. As a result, we observed a low median distance (0.8 kbp) between genes compared with the average distance (6.9 kbp). The ratio between average and median intergenic distances in different eukaryotes makes it clear that Chondrus presents an exceptionally low gene density and a high degree of clustering (Fig. 1B). The proximity of coding ORFs is enhanced by short untranslated regions (on average 142 bp). Although different in size, the C. merolae and Chondrus genomes are similar in that they are regionally compact with few introns and a limited number of genes compared with other eukaryotic species (Table 1). Therefore it is possible that red macroalgae (and other non-Cyanidiales red algae) share with C. merolae a common ancestor that had a reduced genome and that the expansion of the size of the macroalgal genome [red macroalgal genome sizes are 80–1,200 Mbp (22)] occurred after the separation from Cyanidiales.
Recent Genome Expansion Resulting from Transposable Element Invasion.
Repeated sequences constitute 73% of the Chondrus genome. The most abundant transposable elements are class I LTR retrotransposons, representing 58 Mbp; non-LTR retroelements were found also. Twenty-one families of terminal inverted repeat elements (class II elements), representing 13 Mbp of the genome, were found, as was one active helitron family. The retrotransposon component of the genome is extremely complex, not only because of the enormous number of recently transposed elements but also because each family has members that have diverged significantly. The analysis showed evidence for an ongoing burst of transposition activity that is responsible for at least 18 Mbp of the genome. The histogram of the similarity between LTRs shows a unimodal distribution, indicating that the transposition of all elements occurred concomitantly and is very recent (SI Appendix, Fig. S2.3). The mean similarity is 98%, with well over 100 elements exhibiting identical LTRs. The sizes of the copia and gypsy reference elements also are remarkably similar, suggesting a low rate of occurrence of insertions/deletions. Together these results indicate that LTR retroelements have been a major driving force in shaping the genome of Chondrus and that their proliferation has increased the genome size significantly in the last 300,000 y (SI Appendix, Fig. S2.3).
Reduced Gene Content.
In agreement with the compact structure of its genome, there are many examples of reduced gene diversity in Chondrus. For example, we did not find typical and widespread eukaryotic genes such as those for selenoproteins, the machinery for DNA methylation, sulfatases, core components of the endocytic machinery (Rab5 GTPase, AP-2 adaptor complex, endocytic Qc-SNARE), heterotrimeric G proteins, or flagella-specific genes (red algae lack flagella in all life cycle phases). In addition, and surprisingly for a photosynthetic organism, only one photoreceptor was found, a cryptochrome, andChondrus therefore seems to lack most of the photoreceptor types known to date, including aureochromes, phytochromes, rhodopsin, or phototropins. Furthermore, most gene families are small, with few paralogs involved in a given functional process. For example, Chondrus encodes 82 genes for cytoplasmic ribosomal proteins, compared with 349 in Arabidopsis thaliana, even though nearly all ribosomal protein types are present in Chondrus (SI Appendix, Table S4.8). Starch metabolism is another example of the use of a minimum set of genes for a function (see below). The number of transcription factors and transcriptional regulators encoded also is small: 193 proteins, compared with 161 in the unicellular red alga C. merolae, 401 in the multicellular brown alga Ectocarpus siliculosus, which has similarly complex morphology, and more than 1,500 in the morphologically more complex embryophyte A. thaliana (23). Even though the number of transcription factors is limited, it is worth noting that both Dicer and Argonaute, genes, which are involved in small RNA processing (24), are found in the genome. Argonaute genes have not been described in unicellular red algae, glaucophytes, or most prasinophytes, and Dicer cannot be detected in any other red, green, or unicellular heterokont algae (23). This observation suggests a complex regulation by miRNAs in Chondrus, comparable to that found in multicellular plants and animals.
Taken together, these findings prove that pathway simplification, along with gene and intron losses, is ancestral to rhodophytes and not derived in Cyanidiales and other unicellular red algal lineages.
Large Unexplored Gene Diversity.
This study provides an insight into the large number of hitherto unknown genes found in Chondrus, i.e., the 52% of genes that had no counterpart (blastp e-value >10−5) in GenBank. The predicted proteins in the Chondrus genome were compared with the 5,064 proteins from C. merolae (25), the 23,961 predicted proteins of Calliarthron tuberculosum (26), and the 839 proteins of Pyropia(Porphyra) yezoensis present in GenBank. This set of proteins was completed with 22,431 ESTs of P. yezoensis and 36,167 ESTs of Porphyridium cruentum (26) (for details, see SI Appendix). As shown in Fig. 2, 57% of Chondrus orthology groups were not found in other red algae, demonstrating large gene diversity even within this lineage.
Unique Carbohydrate Metabolism.
The Chondrus genome contains 31 glycoside hydrolases (GH) and 65 glycosyltransferases (GT) belonging to 16 GH and 27 GT families, respectively (SI Appendix, Table S7.13). These enzymes are involved in cell-wall metabolism and in the synthesis of other polysaccharides as well as protein and lipid glycosylation. Chondrus features all the genes needed to synthesize and recycle starch (SI Appendix, Table S7.14) but with a surprisingly low redundancy. The finding of only 12 starch-related genes revolutionizes our understanding of the building of this important polymer. Indeed, until very recently it was assumed that the complexity of starch metabolism in the green lineage reflected the complexity of the structure of starch granules. The Chondrus genome clearly invalidates this hypothesis.
One gene homologous to family GT7 chondroitin synthase and nine genes similar to carbohydrate sulfotransferases (CSTs) were identified. These enzymes are involved in the biosynthesis of sulfated polysaccharides, glycosaminoglycans, in animals, suggesting that their Chondrus homologs are involved in carrageenan biosynthesis. CSTs also are conserved in brown algae but are absent in available genomes of terrestrial plants. The clustering of red algal CSTs with those of animals and brown algae (SI Appendix, Figs. S7.3–S7.5) confirms that the synthesis of sulfated polysaccharides is an ancient eukaryotic capacity which has been lost by plants during the conquest of land (27). In addition, Chondrus possesses 12 galactose-6-sulfurylases, which are responsible for the last step of carrageenan biosynthesis and are unique to red algae (28), and three GH16 enzymes related to κ-carrageenases from marine bacteria (29), which putatively are involved in cell-wall expansion and recycling.
Chondrus contains two cellulose synthases (CESA) similar to those of the red algae Porphyra sp. (55% identity) and Griffithsia monilis (62% identity). Like the CESA from G. monilis, the Chondrus CESAs display a CBM48 in N terminus (30). In a Blast search against the NR database, the closest homologs of red algal sequences are CESA from Oomycetes (∼35% identity), from Dictyostelium spp. (∼30% identity), and from various bacteria (∼28% identity). In contrast, CESA from land plants are more distant (∼20% identity). A phylogenetic analysis with the bacterial CESAs as outgroup indicates that CESA and cellulose synthase-like proteins (CSL) from Chloroplastida diverge into two unrelated clades (Fig. 3). The first clade encompasses CESA and CLSB, D, E, F, G, and H and likely derived from the single cellulose synthase of charophytes. The second clade, which includes CSLA and CSLC, originates from a CSL from chlorophytes which is not found in the transcriptomes of charophytes (31). Red algal CESA emerge together with CESA from oomycetes in a distinct cluster rooted by CESA from Amoebozoa, confirming the tendency observed in blastp searches. Therefore, the CESAs from red algae and from green algae and embryophytes have different origins. Amoebozoa were not involved in the primary plastid endosymbiosis; thus acquisition of the bacterial cellulose synthase likely occurred before the primary endosymbiosis, and is not necessarily of cyanobacterial origin (32, 33). The nature of the different ancestral bacteria involved in horizontal gene transfer (HGT) with red algae and green algae is difficult to resolve, because all bacterial cellulose synthesis A (bCsA) genes tend to cluster together in an unrooted tree. Chondrus lacks family GH9 cellulases, which are found in land plants. In contrast, the genome contains three other families of cellulases (GH5, GH6, and GH45), which are absent in Chloroplastida but are conserved in various bacteria and heterotrophic eukaryotes. Phylogenetic analyses confirm that the GH5 cellulases emerge in a clade encompassing cellulases from oomycetes, Amoebozoa, and Nematoda, whereas red algal GH45 cellulases are related to cellulases from fungi (Fig. 3). GH6 cellulases from Chondrus are conserved both in bacteria and fungi but seem closer to bacterial GH6 cellulases. Because at least the red algal GH5 and GH45 cellulases share common ancestors with cellulases from opisthokonts or Amobozoa, these proteins are ancient eukaryotic enzymes predating the primary plastid endosymbiosis. Thus, these ancestral cellulases probably were involved initially in the degradation of bacterial cellulose. After the acquisition of the cellulose biosynthetic pathway, these red algal enzymes likely evolved to participate in cell-wall remodeling.
Unusual Metabolic Features.
Because of their evolutionary history and their habitat, red algae feature some uncommon enzymes related to primary and secondary metabolism. As an illustration, the Chondrusgenome contains a gene similar to the mannosylglycerate synthase (MGS) from the marine bacteriumRhodothermus marinus (48% identity) and from some Archaea (∼29% identity). This family GT78 enzyme synthesizes mannosylglycerate, an osmolyte required for thermal adaptation in thermophilic microorganisms (34, 35). This rare compound is known in red algae as “digeneaside” and accumulates during photosynthesis (36). MGS are not found in the available genomes of glaucophytes, green algae, or land plants, with the exception of Physcomitrella patens and Selaginella moellendorffii. Nonetheless, we have identified GT78 homologs in transcriptomic data of five other red algae and five streptophyte algae. A phylogenetic analysis indicates that the GT78 sequences from red algae, streptophytes, mosses, and lycophytes constitute two distinct clades, rooted by the MGS from R. marinus (SI Appendix, Fig. S7.2). Thus, there was a lateral transfer between a common ancestor of green and red algae with a thermophilic marine bacterium. Most extant red algae retained this enzyme; in the green lineage this gene was lost early by chlorophytes, but it was conserved by streptophytes, mosses, and lycophytes. It finally was lost by land plants after the divergence from lycophytes.
Several sets of anabolic and catabolic reactions previously considered specific to plants or animals were found in Chondrus. This result raises intriguing questions about the biological roles and the regulation of the related genes, molecules, and metabolic pathways, in particular whether their functions and mechanisms of action are conserved across different lineages. Examples are the C18 (plant-like) and C20 (animal-like) oxylipins and related compounds that have been identified in Chondrus in the context of studies on biotic stress response (28, 29). Interestingly, only two genes encoding lipoxygenase (SI Appendix, Table S7.10) have been identified, a surprising result given the diversity of oxylipins observed in this alga. The presence of methyl jasmonate, a plant hormone involved in stress signaling, has been detected in vitro after incubation with linolenic acid (37, 38). However, no candidates for allene oxide synthase, allene oxide cyclase, or jasmonic acid carboxyl methyltransferase were found. This outcome indicates that methyl jasmonate and oxylipin synthesis in Chondrus may be carried out by enzymes other than the ones characterized so far.
Despite the overall reduced genome, a number of gene families have remained diverse or were subject to recent diversification and expansion. One example of this diversity is the comparatively large set of genes related to halogen metabolism. Halogens play an important role in the metabolism of marine red algae (9), and transcriptomic data indicate that the corresponding genes are highly expressed (S1 Appendix, Table S8.1). For example, 20 genes encoding animal-like heme peroxidase homologs were identified (SI Appendix, Fig. S8.4). In mammals these genes play a major role during pathogen ingress, releasing hypohalous acids (39), but their function in red algae is unknown. To our knowledge, animals and marine bacteria are the only groups of organisms in which this type of protein has been found. Their occurrence in Chondrus provides additional evidence for the hypothesis that proteins from the peroxidase-cyclooxygenase superfamily (such as heme peroxidases) have an ancient origin (40). In addition, the Chondrus genome encodes 15 members of the phosphatidic acid phosphatase type 2-haloperoxidase family. Interestingly, it also harbors a group of haloalkane dehalogenase and haloacid dehalogenase enzymes, which remove halogens from alkanes. This group of enzymes previously has been found only in prokaryotes and in the brown seaweed E. siliculosus(41). The large size of these halogen-related gene families likely is a specific evolutionary adaptation to the marine environment, allowing brown and red macroalgae to take benefit of halide chemistry and to modulate finely halogen metabolism, which plays an important role in defense reactions, redox reactions, and the production of secondary metabolites. Supporting this hypothesis are the facts that E. siliculosus has a similarly rich repertoire of peroxidases and haloperoxidases, with ∼16 representatives (41), and that brown algae in general have an active halogen metabolism (42).
The Chondrus genome sheds lights on the early evolution of Archaeplastida. The presence of cellulase families GH5 and GH45 in Chondrus supports the notion that the ancestor of the Archaeplastida was a cellulolytic protist feeding on bacterial exopolysaccharides such as cellulose. This hypothesis is consistent with the ancient eukaryotic origin of family GH9 cellulases (43). After their divergence, red algae only kept GH5 and GH45 cellulases, and green algae and plants lost these genes and conserved GH9 cellulases. Repeated exposition to bacterial genomic DNA also could explain the HGTs of various bacterial origins found in the Chondrus genome (e.g., GT2, GT78). Cellulose biosynthesis was acquired independently in red algae and green algae; independent acquisition could partially explain the structural diversity of cellulose-synthesizing enzyme complexes and cellulose microfibrils in Archaeplastida (44).
The compact structure of the nonrepetitive part of the Chondrus genome and genes also indicates that the red algal lineage went through an evolutionary bottleneck (Fig. 4). Early in the evolution of red algae, but after their divergence from green algae, selective pressure for small physical size or low nutrient requirements probably caused a reduction of the genome, with loss of introns and intergenetic material. This bottleneck also could explain the lack of flagella in all life-cycle stages in red algae, because the corresponding genes may have been lost during the genome compaction. It has been suggested previously (45) that, because of the limited low pH tolerance of cyanobacteria, early eukaryotic algae would have had less competition in acidic environments where fewer photosynthetic organisms were present. The extant red algae C. merolae or Galdieria sulphuraria live in an environment with high temperature and low pH, and even though it is not obvious why such conditions would reduce genome size, it is clear that these conditions favor compact genomes in red algae and may indicate that the ancestral red alga was an acido- and thermophilic organism. The evolutionary bottleneck also might explain the high number of orphan genes in the genome, because red algae were forced to reinvent gene functions that were lost during the genome reduction. If this hypothesis is correct, we predict that the ongoing red algal genome projects on Porphyra spp (6), P. cruentum (46), and C. tuberculosum (47) will show similar gene and genome organization.
In conclusion, this study presents a reference genome for a multicellular red alga and provides a number of unexpected insights into the origin and evolution of this ancestral plant lineage. It also provides fundamental data on the unique metabolic pathways of this large and economically important group of marine algae. In addition, because of its unique genome characteristics, C. crispus constitutes a novel model species for studying the complex evolutionary forces that shape eukaryotic genomes. Finally, as an archive of the gene content of ancestral marine plants, this genome will help comparatively delineate the innovations that were necessary for the emergence of land plants and their adaptation to the terrestrial environments.
Materials and Methods
A gametophyte of C. crispus Stackhouse (Gigartinales) was collected at Peggy’s Cove, Nova Scotia, Canada (44°29′31′′N, 63°55′11′′W) in 1985 by Juan Correa and since then has been growing vegetatively in unialgal culture.
The main raw data are 14-fold coverage shotgun reads sequenced with Sanger sequencing produced from five libraries with various insert sizes (SI Appendix, Table S1.1). Their assembly with ARACHNE (48) generated a collection of 925 scaffolds, covering 104.8 Mbp. An automated annotation based partially on 300,000 cDNA reads was performed and was used as a basis for expert annotation. For details on the different analyses and available data, see SI Appendix. An outline of SI Appendix content is shown in Fig. 5.
We thank Pr. Juan Correa (Pontificia Universidad Católica de Chile) for providing the sequenced strain. This work was supported by funding from IDEALG Grants ANR-10-BTBR-04-02 and 04-04 “Investissements d’avenir, Biotechnologies-Bioressources,” Groupement d’Intérêt Scientifique Génomique Marine, NERC NE/J00460X/1, Network of Excellence Marine Genomics Europe (GOCE-CT-2004-505403), Conseil Regional de Bretagne, and the Czech Science Foundation. A.Z. was supported by a bursary grant from the Scottish Association for Marine Science, travel grants from the Seventh Framework Program Association of European Marine Biological Laboratories (ASSEMBLE), and a The Marine Alliance for Science and Technology for Scotland (MASTS) Visiting Researcher Fellowship. C.M.M.G. was supported by Grant Natural Environment Research Council NE/J00460X/1. This work was supported by funding from the Commissariat à l’Energie Atomique (CEA).
- 1To whom correspondence should be addressed. E-mail: [email protected].
Author contributions: J.C., B.P., T.T., G.M., B.N., K.V., J.-M.A., J.H.B., F.-Y.B., J.M.C., B.K., C.L., P.W., and C.B. designed research; J.C., B.P., W.C., S.G.B., C. Chaparro, T.T., T.B., G.M., B.N., K.V., M.E., F.A., A.A., J.-M.A., J.F.B.-N., J.H.B., F.-Y.B., L.B., F.C.-H., S.C.-G., B.C., L.C., J.M.C., S.M.C., C. Colleoni, M.C., C.D.S., L.D., F.D., P.D., S.M.D., T.G., C.M.M.G., A.G., C.H., K.J., M.K., N.K., K.L., C.L., P.J.L., A.M., O.P., F.P., J.P., S.A.R., S.R., G.S., J.W., A.Z., P.W., and C.B. performed research; B.P. and W.C. contributed new reagents/analytic tools; J.C., B.P., W.C., S.G.B., C. Chaparro, T.T., T.B., G.M., B.N., K.V., M.E., F.A., A.A., J.-M.A., J.F.B.-N., J.H.B., F.-Y.B., L.B., F.C.-H., S.C.-G., B.C., L.C., J.M.C., S.M.C., C. Colleoni, M.C., C.D.S., L.D., F.D., P.D., S.M.D., T.G., C.M.M.G., A.G., C.H., K.J., M.K., B.K., N.K., K.L., C.L., P.J.L., D.H.M., L.M.-C., A.M., Z.N., P.N.C., O.P., F.P., J.P., S.A.R., G.S., A.S., J.W., A.Z., P.W., and C.B. analyzed data; and J.C., S.G.B., T.T., T.B., G.M., M.E., and C.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1221259110/-/DCSupplemental.
If you are unfamiliar with the name, bladderwrack is actually a common type of seaweed similar to kelp. It exhibits a number of potential health benefits including thyroid health, improved metabolism and circulation. It is also an anti-inflammatory and antioxidant food that can help strengthen the bones, improve heart health and prevent you from aging prematurely.
WHAT IS BLADDERWRACK?
Bladderwrack thrives in various parts of the world’s oceans. It is commonly found around Europe, the British Isles, and in the Baltic sea while it is also seen around North America’s eastern coast. I personally love the name ‘bladderwrack’ but it is also known around the world as red fucus, rockweed and black tang or by its botanical name ‘Fucus vesiculosus’.
Bladderwrack thrives best in shallow, sheltered inlets where there is little water movement and can be found in very large masses in some areas. For anybody that wants to do some collecting, bladderwrack is easy enough to identify by the paired air sacks seen on its midrib branches.
Although it is nowhere near as well known as many herbal remedies or even other types of seaweed, bladderwrack has been used as a medicinal remedy for many long year. Bladdewrack is very rich in iodine and was a very early source of this important mineral.
Iodine is essential in thyroid health and treating numerous illnesses and is also an important part of a healthy diet. As well as iodine, it is a great source of natural antioxidants and minerals like beta-carotene and potassium, magnesium, calcium and iron. Bladderwrack also contains some of the B family vitamins and small quantities of vitamins A, C, K and E.
Despite being used for centuries; it has only recently caught the eye of the general public and demand is on the up. It is available in several different forms most commonly as a supplement or powder that you can consume directly or mix with water.
BLADDERWRACK HEALTH BENEFITS
1. FOR THYROID HEALTH
Back during the 19th century in the days before modern medicine, bladderwrack was used as the original iodine source for medicinal purposes. Iodine is absolutely essential for the health of your thyroid and to ensure that your hormones and metabolism remain in healthy balance.
Because bladderwrack is such a rich source of iodine, it can be used to treat a variety of thyroid conditions which help control your metabolic and hormonal balance. Bladderwrack essentially works by stimulating the thyroid and allowing it to produce sufficient hormones.
2. FOR WOMEN’S HEALTH
When it comes to female health, bladderwrack offers plenty of potential. Iodine is necessary if the thyroid is to do its job properly and produce sufficient hormones. This is significant in terms of women’s health as a lack of hormones can hinder ovulation.
Poor thyroid function during pregnancy can have a detrimental effect on both the mother’s blood pressure and mental function of the unborn child.
Another function of iodine its use for treating fibrocystic breast disease – one of the leading causes of breast cancer. According to studies, bladderwrack has a similar function to soy in regulating a female’s sex organs making it a safe alternative to soy. (1)
The same study linked above found that bladderwrack helped women with a history of short and light menstrual cycles. Those who took 1.4g of bladderwrack each day experienced considerably longer periods. Moreover, women who took bladderwrack produced less estrogen but increased their levels of progesterone.
Progesterone prepares a woman’s uterus lining for fertilization each month. Without sufficient amounts of the hormone, they are unable to conceive.
Note however that there are safety concerns regarding bladderwrack during pregnancy and pregnant women should only take it under medical supervision.
3. FOR INFLAMMATORY CONDITIONS
Bladderwrack has natural anti-inflammatory properties and it has been used down the years to treat various internal and external inflammatory conditions. For people with painful joints caused by conditions like gout or arthritis, bladderwrack may be just what they need to ease the pain and move more freely.
Bladderwrack can also help treat inflammatory skin problems and hemorrhoids in a safe and natural way. Depending on the type of inflammation you are trying to treat, bladderwrack can be taken internally or topically applied to the skin.
4. FOR DIGESTIVE HEALTH
We are all aware of the importance of fiber as it relates to overall health and digestive health in particular. Unfortunately that does not mean that we take heed and get enough of it. Bladderwrack is a great source of several types of healthy fiber including a fibber called alginic acid. Alginic acid has a very beneficial effect on digestion.
It can add bulk to the food passing through the bowels help relieve constipation. It also improves nutritional uptake making the food we eat more beneficial to our bodies. Bladderwrack can also help ease bloating and flatulence while it is also considered effective for painful stomach cramps and gastric ulcers.
5. FOR HEART HEALTH
According to research, bladderwrack can help increase the levels of ‘good’ HFL cholesterol in the blood. By improving your cholesterol, this healthful seaweed can protect the heart from many killer diseases like atherosclerosis, heart attack and stroke.
It may also have a knock on positive effect on your blood pressure especially in people with hypertension which protects you from heart disease and means your cardiovascular system is put under less strain.
6. FIBER CONTENT
Bladderwrack contains large amounts of a unique form of fiber called fucoidan. Fucoiidan has been linked to a number of different health benefits including a reduction in cholesterol, reduced blood sugar and may even have anti-tumor effects.
Fucoidan helps to regulate the substance responsible for the reproduction if cells and their growth. In theory, fucoidan slows the growth of harmful cells meaning that it can hinder the proliferation of cancer.
7. FOR OBESITY AND WEIGHT CONTROL
As well as being high in fiber and possessing very few calories, bladderwrack can stimulate the metabolism making it a great way to lose weight. If your body is functioning at a higher level, it uses more energy and burns quickly through its fat reserves.
Some people say that bladderwrack helps you to feel sated and suppresses the appetite.This means that you will eat fewer calories throughout the day and in time….lose more weight.
Of course there is no cure all for obesity and simply adding one food stuff to the diet is unlikely to have significant effects unless you use it as part of an overall diet and exercise plan.
8. FOR BETTER VISION
As we have already mentioned, bladderwrack is a good source of beta-carotene. This is an antioxidant pigment responsible for giving certain fruit and vegetables their rich colors. Beta-carotene is known to improve eye health and vision by neutralizing the damaging effect of free radicals on the eyes. It helps to slow down the macular degeneration that comes with aging and can prevent cataracts from developing.
Bladderwrack has numerous valuable nutrients that can help you feel and appear younger for longer. It is also a great source of natural antioxidants which are known to help your skin’s appearance. Taking bladderwrack supplements can reduce the appearance of age spots, wrinkles and other unsightly skin blemishes. It also helps to tighten the skin and keep it more elastic even as you age.
Not only do antioxidants improve your appearance but they also help to combat the damage done to your insides from the harmful free radicals we can’t help but encounter every day.Natural antioxidants of the type found in bladderwrack and many other natural products can protect against disease and even reverse the damage done.
- Iodine is a key component of thyroid hormones, which are required throughout life for normal growth, neurological development, and metabolism. (More information)
- Insufficient iodine intake impairs the production of thyroid hormones, leading to a condition called hypothyroidism. Iodine deficiency results in a range of adverse health disorders with varying degrees of severity, from thyroid gland enlargement (goiter) to severe physical and mental retardation known as cretinism. (More information)
- Iodine deficiency-induced hypothyroidism has adverse effects in all stages of development but is most damaging to the developing brain. Maternal iodine deficiency during pregnancy can result in maternal and fetal hypothyroidism, as well as miscarriage, preterm birth, and neurological impairments in offspring. (More information)
- Even in areas with voluntary/mandatory iodization programs and in iodine-replete countries, pregnant women, lactating mothers, and young infants are among the most vulnerable to iodine deficiency due to their special requirements during these life stages. (More information)
- The recommended dietary allowance (RDA) for iodine intake is 150 micrograms (μg)/day in adults, 220 μg/day in pregnant women, and 290 μg/day in breast-feeding women. During pregnancy and lactation, the fetus and infant are entirely reliant on maternal iodine intake for thyroid hormone synthesis. (More information)
- Thyroid accumulation of radioactive iodine (131I) increases the risk of developing thyroid cancer, especially in children. In case of radiation emergencies, current preventive measures include the distribution of pharmacologic doses of potassium iodide that would reduce the risk of significant uptake of 131I by the thyroid gland. (More information)
- Seafood is an excellent source of dietary iodine. Dairy products, grains, eggs, and poultry contribute substantially to dietary iodine intakes in the US. (More information)
- More than 120 countries worldwide have introduced programs of salt fortification with iodine in order to correct iodine deficiency in populations. (More information)
- In iodine-deficient populations, a rapid increase in iodine intake may precipitate iodine-induced hyperthyroidism. The risk of iodine-induced hyperthyroidism is especially high in older people with multi-nodular goiter. (More information)
- In iodine-sufficient adults, long-term iodine intake above the tolerable upper intake level (UL) of 1,100 μg/day may increase the risk of thyroid disorders, including iodine-induced goiter and hypothyroidism. (More information)
Iodine (I), a non-metallic trace element, is required by humans for the synthesis of thyroid hormones. Iodine deficiency is an important health problem throughout much of the world. Most of the Earth’s iodine, in the form of the iodide ion (I–), is found in oceans, and iodine content in the soil varies with region. The older an exposed soil surface, the more likely the iodine has been leached away by erosion. Mountainous regions, such as the Himalayas, Atlas, Andes, and Alps; flooded river valleys, such as the Ganges River plain in India; and many inland regions, such as central Asia and Africa, central and eastern Europe, and the Midwestern region of North America are among the most severely iodine-deficient areas in the world (1).
Iodine is an essential component of the thyroid hormones, triiodothyronine (T3) and thyroxine (T4), and is therefore essential for normal thyroid function. To meet the body’s demand for thyroid hormones, the thyroid gland traps iodine from the blood and incorporates it into the large (660 kDa) glycoprotein thyroglobulin. The hydrolysis of thyroglobulin by lysosomal enzymes gives rise to thyroid hormones that are stored and released into the circulation when needed. In target tissues, such as the liver and the brain, T4 (the most abundant circulating thyroid hormone) can be converted to T3by selenium-containing enzymes known as iodothyronine deiodinases (DIOs) (Figure 1; see also Nutrient interactions). T3is the physiologically active thyroid hormone that can bind to thyroid receptors in the nuclei of cells and regulate gene expression. In this manner, thyroid hormones regulate a number of physiologic processes, including growth, development, metabolism, and reproductive function (2).
The regulation of thyroid function is a complex process that involves the hypothalamus and the pituitary gland. In response to thyrotropin-releasing hormone (TRH) secretion by the hypothalamus, the pituitary gland secretes thyroid-stimulating hormone (TSH), which stimulates iodine trapping, thyroid hormone synthesis, and release of T4 and T3 by the thyroid gland. The presence of adequate circulating T4 and T3 feeds back at the level of both the hypothalamus and pituitary, decreasing TRH and TSH production (Figure 2). When circulating T4 levels decrease, the pituitary gland increases its secretion of TSH, resulting in increased iodine trapping, as well as increased production and release of both T3 and T4. Iodine deficiency results in inadequate production of T4. In response to decreased blood T4 concentrations, the pituitary gland increases its output of TSH. Persistently elevated TSH levels may lead to hypertrophy (enlargement) of the thyroid gland, also known as goiter (see Deficiency) (3).
The thyroid gland of a healthy adult concentrates 70-80% of a total body iodine content of 15-20 mg and utilizes about 80 μg of iodine daily to synthesize thyroid hormones. In contrast, chronic iodine deficiency can result in a dramatic reduction of the iodine content in the thyroid well below 1 mg (1). Iodine deficiency is recognized as the most common cause of preventable brain damage in the world. The spectrum of iodine deficiency disorders (IDD) includes mental retardation, hypothyroidism, goiter, and varying degrees of other growth and developmental abnormalities (4). The World Health Organization (WHO) estimated that over 30% of the world’s population (2 billion people) have insufficient iodine intake as measured by median urinary iodine concentrations below 100 μg/L (5). Moreover, about one-third of school-age children (6-12 years old) worldwide (241 million children in 2011) have insufficient iodine intake (6, 7). Major international efforts have produced dramatic improvements in the correction of iodine deficiency in the 1990s, mainly through the use of iodized salt in iodine-deficient countries (4). Although about 70% of households in the world now have access to iodized salt (8), mild-to-moderate iodine deficiency remains a public health concern in at least 30 countries; there are no iodine excretion data available for 42 other countries, including Israel, Syria, and Sierra Leone (7). For more information on the international effort to eradicate iodine deficiency, visit the websites of the Iodine Global Network (formerly the International Council for the Control of Iodine Deficiency Disorders) and the WHO.
More than 90% of ingested iodine is excreted in the urine within 24-48 hours such that daily iodine intakes in a population can be extrapolated from measures of median spot urinary iodine concentrations (9, 10). According to WHO criteria, population iodine deficiency is defined by median urinary iodine concentrations lower than 150 micrograms (μg)/L for pregnant women and 100 μg/L for all other groups (Table 1). Adequate intakes correspond to median urinary iodine concentrations of 100-199 μg/L in school-age children and 150-249 μg/L in pregnant women (Table 1). While median urinary iodine concentration is a population indicator of recent dietary iodine intake, multiple collections of 24-hour urinary iodine are preferable to estimate intake in individuals (9-11).
|Population Group||Median/Range of Urinary Iodine Concentrations (μg/L)||Iodine Intake|
|Children (<2 years)||<100||Insufficient|
|Children (≥6 years), adolescents, and adults*||<100||Insufficient|
|200-299||More than adequate|
|250-499||More than adequate|
|*Excludes pregnant or lactating women.
#Given that iodine requirements are increased in breast-feeding women (see The RDA), the numbers for median urinary excretion concentrations are lower than one would expect because iodine is also excreted in breast milk.
In many countries, serum TSH concentration is used in the screening for congenital hypothyroidism in newborns. Newborn TSH can be used as an indicator of population iodine status. Yet, in older children and adults, serum TSH is not a sensitive indicator of iodine status as concentrations are usually maintained within a normal range despite frank iodine deficiency (12). Serum thyroglobulin concentration in school-age children is a sensitive marker of iodine status in populations (13). In areas of endemic goiter, changes in thyroid size reflect long-term iodine nutrition (months to years). Assessment of the goiter rate in a population is used to define the severity of iodine deficiency, as well as to monitor the long-term impact of sustained salt iodization programs (4, 10). Finally, serum thyroid hormone concentrations do not adequately reflect iodine nutrition in populations (1).
All the adverse effects of iodine deficiency in animals and humans are collectively termed iodine deficiency disorders (reviewed in 1). Thyroid enlargement, or goiter, is one of the earliest and most visible signs of iodine deficiency. It is a physiologic adaptation of the thyroid gland in response to persistent stimulation by TSH (see Function). In mild iodine deficiency, thyroid enlargement may be enough to maximize the uptake of available iodine and provide the body with sufficient thyroid hormones. Yet, large goiters can obstruct the trachea and esophagus and damage the recurrent laryngeal nerves.
More severe cases of iodine deficiency result in impaired thyroid hormone synthesis known as hypothyroidism. Adequate iodine intake will generally reduce the size of goiters, but the reversibility of the effects of hypothyroidism depends on an individual’s life stage. Iodine deficiency-induced hypothyroidism has adverse effects in all stages of development but is most damaging to the developing brain. In addition to regulating many aspects of growth and development, thyroid hormones are important for the migration, proliferation, and differentiation of specific neuronal populations, the overall architecture of the brain’s cortex, the formation of axonal connections, and the myelination of the central nervous system, which occurs both before and shortly after birth (reviewed in 14).
The effects of iodine deficiency at different life stages are discussed below.
Daily iodine requirements are significantly increased in pregnant and breast-feeding women because of (1) the increased thyroid hormone production and transfer to the fetus in early pregnancy before the fetal thyroid gland becomes functional, (2) iodine transfer to the fetus during late gestation, (3) increased urinary iodine excretion, and (4) iodine transfer to the infant via breast milk (see also The RDA) (12, 15).
During pregnancy, the size of the thyroid gland is increased by 10% in women residing in iodine-sufficient regions and increased by 20%-40% in those living in iodine-deficient regions (16). Iodine deficiency during pregnancy can result in hypothyroidism in women. Maternal hypothyroidism has been associated with increased risk for preeclampsia, miscarriage, stillbirth, preterm birth, and low-birth-weight infants (reviewed in 16). In addition, severe iodine deficiency during pregnancy may result in congenital hypothyroidism and neurocognitive deficits in the offspring (see Prenatal development) (12).
Iodine-deficient women who are breast-feeding may not be able to provide sufficient iodine to their infants who are particularly vulnerable to the effects of iodine deficiency (see Newborns and infants) (17). A daily prenatal supplement of 150 μg of iodine, as recommended by the American Thyroid Association (ATA) (16), will help to ensure that US pregnant and breast-feeding women consume sufficient iodine during these critical periods. In iodine-deficient areas where iodized salt is not available, the Iodine Global Network (IGN; formerly the International Council for the Control of Iodine Deficiency Disorders), the World Health Organization (WHO), and UNICEF recommend that lactating women receive a single annual dose of 400 mg of iodine (or 250 μg/day) and exclusively breast-feed for at least six months. When breast-feeding is not possible, direct supplementation of the infant (<2 years old) with a single annual dose of 200 mg of iodine (or 90 μg/day) is advised (4). A randomized and placebo-controlled trial recently demonstrated that maternal supplementation (with a single 400-mg dose of iodine) improved the iodine status of breast-fed infants more efficiently than direct infant supplementation (with a single 100 mg-dose of iodine) for a period of at least six months (18). Yet, supplementation of lactating women failed to increase maternal urinary iodine concentrations above 100 μg/L, suggesting that supplemented mothers remained deficient in iodine (18).
Fetal iodine deficiency is caused by iodine deficiency in the mother (see Pregnancy and lactation). During pregnancy, before the fetal thyroid gland becomes functional at 16-20 weeks’ gestation, maternal thyroxine (T4) crosses the placentato promote normal embryonic and fetal development. Hence, maternal iodine deficiency and hypothyroidism can result in adverse pregnancy complications, including fetal loss, placental abruption, preeclampsia, preterm delivery, and congenital hypothyroidism in the offspring (16). The effects of maternal hypothyroidism on the offspring depend on the timing and severity of in utero iodine deficiency. A severe form of congenital hypothyroidism may lead to cretinism, a condition associated with irreversible mental retardation. The clinical picture of neurological cretinism in the offspring includes severe mental and physical retardation, deafness, mutism, and motor spasticity.
A myxedematous form of cretinism has been associated with coexisting iodine and selenium deficiency in central Africa (see Nutrient interactions) and is characterized by a less severe degree of mental retardation than in neurological cretinism. Yet, affected individuals exhibit all the features of severe hypothyroidism, including severe growth retardation and delayed sexual maturation (12). Two longitudinal cohort studies (one in the UK and one in Australia) recently observed that even mild-to-moderate iodine deficiency during pregnancy was associated with reduced scores of IQ and various measures of literacy performance in children 8 to 9 years of age (19, 20).
Infant mortality is higher in areas of severe iodine deficiency than in iodine-replete regions, and several studies have demonstrated an increase in childhood survival upon correction of the iodine deficiency (8, 21, 22). Infancy is a period of rapid brain growth and development. Sufficient thyroid hormone, which depends on adequate iodine intake, is essential for normal brain development. Even in the absence of congenital hypothyroidism, iodine deficiency during infancy may result in abnormal brain development and, consequently, impaired intellectual development (23, 24).
Children and adolescents
Iodine deficiency in children and adolescents is often associated with goiter. The incidence of goiter peaks in adolescence and is more common in girls than boys. School-age children in iodine-deficient areas show poorer school performance, lower IQs, and a higher incidence of learning disabilities than matched groups from iodine-sufficient areas. Three meta-analyses of mainly cross-sectional studies concluded that chronic iodine deficiency was associated with reduced mean IQ scores by 7-13.5 points in participants (primarily children) (25-27). However, these observational studies did not distinguish between iodine deficiency during pregnancy and during childhood, and such observational studies may be confounded by social, economic, and educational factors that influence child development.
Inadequate iodine intake may also result in goiter and hypothyroidism in adults. Although the effects of hypothyroidism are more subtle in the brains of adults than children, research suggests that hypothyroidism results in poor social and economic achievements due to low educability, apathy, and reduced work productivity (28). Other symptoms of hypothyroidism in adults include fatigue, weight gain, cold intolerance, and constipation.
Finally, because iodine deficiency induces an increase in the iodine trapping capacity of the thyroid, iodine-deficient individuals of all ages are more susceptible to radiation-induced thyroid cancer (see Disease Prevention), as well as to iodine-induced hyperthyroidism after an increase in iodine intakes (see Safety) (2).
While the risk of iodine deficiency for populations living in iodine-deficient areas without adequate iodine fortificationprograms is well recognized, concerns have been raised that certain subpopulations in countries considered iodine-sufficient may not consume adequate iodine (7, 29). The greater use of methods assessing iodine status (see Biomarkers of iodine status) has shown that iodine deficiency also occurs in areas where the prevalence of goiter is low, in coastal areas, in highly developed countries, and in regions where iodine deficiency was previously eliminated (4).
The US is currently considered to be iodine-sufficient. Yet, in recent years, dietary intakes of iodine in the US population have decreased. Data from the latest US National Health and Nutrition Examination Survey (NHANES 2009-2010) indicated that the median urinary iodine concentration for the general population was 144 μg/L compared to 164 μg/L reported in previous assessments (NHANES 2005-2006 and 2007-2008) (30, 31). In addition to regional differences across the US, ethnic variations have been found. In all age groups, median urinary iodine concentrations were shown to be lower in African Americans than in Hispanics and Caucasians.
In addition, median urinary iodine concentrations in nonpregnant women of childbearing age and pregnant women indicate that mild iodine deficiency has re-emerged in the US in recent years (31).
Data from US NHANES 2007-2010 indicated that 37.3% of nonpregnant women (ages 15-44 years) had urinary iodine concentrations lower than 100 μg/L, reflecting potentially insufficient iodine intakes (see Biomarkers of iodine status) (31). Only one-fifth of nonpregnant women reported using iodine-containing supplements in an earlier NHANES (2001-2006) (32). Yet, adequate intakes of iodine in women of childbearing age (150 μg/day; see The RDA) are essential for optimum stores of iodine, especially if they are considering pregnancy. Some experts suggested a daily consumption of 250 μg of iodine before conception to ensure adequate thyroid hormone production and iodine supply to the embryo and fetus during pregnancy (see Pregnancy and lactation) (12).
There are no statistics on the global burden of iodine deficiency in pregnant women, but national and regional data suggest that this group is especially vulnerable. Given the increased iodine requirements during pregnancy, the median urinary iodine concentration should be at least of 150 μg/L (see Biomarkers of iodine status). Pooled data from NHANES 2005-2010 reported that US pregnant women had a median urinary iodine concentration of 129 μg/L, and the lowest median concentration (109 μg/L) was observed during the first trimester of gestation, when the embryo/fetus relies exclusively on maternal thyroid hormones (31).
While data regarding the iodine status of breast-feeding women in the US are limited, dietary intakes that were inadequate during pregnancy are likely to be insufficient in a significant fraction of breast-feeding women (33, 34). A systematic review of the literature recently reported suboptimal dietary iodine intakes in breast-feeding women in some countries with a mandatory fortification program, including Denmark, Australia, and India (35). The American Thyroid Association (ATA) recommends that all North American women who are pregnant or breast-feeding supplement their dietary iodine intake with 150 μg/day of iodine (36).
Breast-fed and weaning infants
The body of a healthy newborn contains only about 300 μg of iodine, which makes newborns extremely vulnerable to iodine deficiency (28), and breast-fed infants are entirely reliant on maternal iodine intakes for thyroid hormonesynthesis. Even in areas covered by a salt iodization program, weaning infants are at high risk of iodine deficiency, especially if they are not receiving iodine-containing infant formula (17).
Individuals consuming special diets
Diets that exclude iodized salt, fish, and seaweed have been found to contain very little iodine (9). Individuals consuming branded weight-loss foods may also be at risk of inadequate intakes (37). A small US cross-sectional study in 78 vegetarians and 63 vegans reported median urinary iodine concentrations of 147 μg/L and 78.5 μg/L, respectively, suggesting inadequate iodine intakes among vegans (38). Two cases of goiter and/or hypothyroidism have also been recently reported in children following restrictive diets to control esophageal inflammation (eosinophilic esophagitis) (39)or allergies (40).
Patients requiring parenteral nutrition
Although iodine is usually not added to parenteral nutrition (PN) solutions, topical iodine-containing disinfectants and other adventitious sources provide substantial amounts of iodine to some PN patients such that the occurrence of iodine deficiency is unlikely. Yet, deficiency might occur, especially in preterm infants with limited body stores, if chlorhexidine-based antiseptics replace iodinated antiseptics (28, 41).
While iodine is an essential component of thyroid hormones, the selenium-containing iodothyronine deiodinases (DIOs) are enzymes (or selenoenzymes) required for the conversion of T4 to the biologically active thyroid hormone, T3 (see the article on Selenium). DIO1 activity may also be involved in regulating iodine homeostasis (43). In addition, glutathione peroxidases are selenoenzymes that protect the thyroid gland from hydrogen peroxide-induced damage during thyroid hormone synthesis (44). A randomized, placebo-controlled study in 151 pregnant women at risk of developing autoimmune thyroid disease found that selenium supplementation (200 μg/day in the form of selenomethionine) at 12 weeks of gestation until 12 months’ postpartum reduced the risk of thyroid dysfunction and permanent hypothyroidism(45). However, another trial (the Selenium in Pregnancy Intervention Trial) found no benefit of selenium supplementation (60 μg/day from 12-14 weeks of gestation to delivery) over placebo on circulating autoantibody concentrations in pregnant women mildly deficient in iodine (46).
The epidemiology of coexisting iodine and selenium deficiencies in central Africa has been linked to the prevalence of myxedematous cretinism, a severe form of congenital hypothyroidism accompanied by mental and physical retardation. Selenium deficiency may be only one of several undetermined factors that might exacerbate the detrimental effects of iodine deficiency (42). Besides, results from randomized controlled intervention trials have shown that correcting only the selenium deficiency may have a deleterious effect on thyroid hormone metabolism in school-age children with co-existing selenium and iodine deficiency (47, 48). Finally, selenium deficiency in rodents was found to have little impact on DIO activities as it appears that selenium is being supplied in priority for adequate synthesis of DIOs at the expense of other selenoenzymes (44).
Severe iron-deficiency anemia can impair thyroid metabolism in the following ways: (1) by altering the TSH response of the pituitary gland; (2) by reducing the activity of thyroid peroxidase that catalyzes the iodination of thyroglobulin for the production of thyroid hormones; and (3) in the liver by limiting the conversion of T4 to T3, increasing T3 turnover, and decreasing T3 binding to nuclear receptors (49). It is estimated that goiter and iron-deficiency anemia coexist in up to 25% of school-age children in west and north Africa (42). A randomized controlled study in iron-deficient children with goiter showed a greater reduction in thyroid size following the consumption of iodized salt together with 60 mg/day of iron four times per week compared to placebo (50). Additional interventions have confirmed that correcting iron-deficiency anemia improved the efficacy of iodine supplementation to mitigate thyroid disorders (reviewed in 42, 49).
In north and west Africa, vitamin A deficiency and iodine deficiency-induced goiter may coexist in up to 50% of children. Vitamin A status, like other nutritional factors, appears to influence the response to iodine prophylaxis in iodine-deficient populations (51). Vitamin A deficiency in animal models was found to interfere with the pituitary–thyroid axis by (1) increasing the synthesis and secretion of thyroid-stimulating hormone (TSH) by the pituitary gland, (2) increasing the size of the thyroid gland, (3) reducing iodine uptake by the thyroid gland and impairing the synthesis and iodination of thyroglobulin, and (4) increasing circulating concentrations of thyroid hormones (reviewed in 52). A cross-sectional studyof 138 children with concurrent vitamin A and iodine deficiencies found that the severity of vitamin A deficiency was associated with higher risk of goiter and higher concentrations of circulating TSH and thyroid hormones (51). These children received iodine-enriched salt together with vitamin A (200,000 IU at baseline and at 5 months) or a placebo in a randomized, double-blind, 10-month trial. Vitamin A supplementation significantly decreased TSH concentration and thyroid volume compared to placebo (51). In another trial, vitamin A supplementation alone (without iodine) to iodine-deficient children reduced the volume of the thyroid gland, as well as TSH and thyroglobulin concentrations (53). Yet, supplemental vitamin A had no additional effect on thyroid function/hormone metabolism when children were also given iodized oil.
Some foods contain substances that interfere with iodine utilization or thyroid hormone production; these substances are called goitrogens. The occurrence of goiter in the Democratic Republic of Congo has been related to the consumption of cassava, which contains linamarin, a compound that is metabolized to thiocyanate and blocks thyroidal uptake of iodine (1). In iodine-deficient populations, tobacco smoking has been associated with an increased risk for goiter (54, 55). Cyanide in tobacco smoke is converted to thiocyanate in the liver, placing smokers with low iodine intake at risk of developing a goiter. Moreover, thiocyanate affects iodine transport into the lactating mammary gland, leading to low iodine concentrations in breast milk and impaired iodine supply to the neonates/infants of smoking mothers (2). Some species of millet, sweet potatoes, beans, and cruciferous vegetables (e.g., cabbage, broccoli, cauliflower, and Brussels sprouts) also contain goitrogens (1). Further, the soybean isoflavones, genistein and daidzein, have been found to inhibit thyroid hormone synthesis (56). Most of these goitrogens are not of clinical importance unless they are consumed in large amounts or there is coexisting iodine deficiency. Industrial pollutants, such as perchlorate (see Safety), resorcinol, and phthalic acid, may also be goitrogenic (1, 57).
The RDA for iodine was reevaluated by the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) in 2001 (Table 2). The recommended amounts were calculated using several methods, including the measurement of iodine uptake in the thyroid glands of individuals with normal thyroid function (9). Similar recommendations have been made by several organizations, including the American Thyroid Association (ATA) (16, 58), the World Health Organization (WHO), the Iodine Global Network (IGN; formerly the International Council for the Control of Iodine Deficiency Disorders), and the United Nations Children’s Fund (UNICEF) (4). Of note, the WHO, IGN, and UNICEF recommend daily intakes of 250 μg of iodine for both pregnant and breast-feeding women (4).
|Life Stage||Age||Males (μg/day)||Females (μg/day)|
|Infants||0-6 months||110 (AI)||110 (AI)|
|Infants||7-12 months||130 (AI)||130 (AI)|
|Adults||19 years and older||150||150|
Radioactive iodine, especially iodine 131 (131I), may be released into the environment as a result of nuclear reactor accidents, such as the 1986 Chernobyl nuclear accident in Ukraine and the 2011 Fukushima Daiichi nuclear accident in Japan. Thyroid accumulation of radioactive iodine increases the risk of developing thyroid cancer, especially in children (59). The increased iodine trapping activity of the thyroid gland in iodine deficiency results in increased thyroid accumulation of radioactive iodine (131I). Thus, iodine-deficient individuals are at increased risk of developing radiation-induced thyroid cancer because they will accumulate greater amounts of radioactive iodine. Potassium iodide administered in pharmacologic doses (up to 130 mg for adults) within 48 hours before or eight hours after radiation exposure from a nuclear reactor accident can significantly reduce thyroid uptake of 131I and decrease the risk of radiation-induced thyroid cancer (60). The prompt and widespread use of potassium iodide prophylaxis in Poland after the 1986 Chernobyl nuclear reactor accident may explain the lack of a significant increase in childhood thyroid cancer compared to fallout areas where potassium iodide prophylaxis was not widely used (61). In the US, the Nuclear Regulatory Commission (NRC) requires that consideration be given to potassium iodide as a protective measure for the general public in the case of a major release of radioactivity from a nuclear power plant (62). See also the US FDA’s Potassium Iodide Information.
Fibrocystic breast changes constitute a benign (non-cancerous) condition of the breasts, characterized by lumpiness and discomfort in one or both breasts. Cyst formation and fibrous changes in the appearance of breast tissue occur in at least 50% of premenopausal women and are not usually associated with an increased risk of breast cancer (63). The cause of fibrocystic changes is not known, but variations in hormonal stimulation during menstrual cycles may trigger changes in breast tissue (63).
A few observational studies also suggested an association between benign breast diseases (including but not limited to fibrocystic changes) and thyroid disorders. Recently, a small case-control study (166 cases vs. 72 controls) showed that the frequency of benign breast diseases was greater in women with nodular goiter (54.9%) or Hashimoto thyroiditis (47.4%) than in euthyroid controls (29.2%) (64). Conversely, the prevalence of anti-thyroid autoimmunity and hypothyroidism was found to be significantly higher in women with benign breast diseases compared to controls (65, 66). Interestingly, correcting hypothyroidism with supplemental T4 was found to improve some of the benign breast disease symptoms, including breast pain (mastalgia) and nipple discharge (65).
In estrogen-treated rats, iodine deficiency leads to changes similar to those seen in fibrocystic breasts, while iodine repletion reverses those changes (67). An uncontrolled study of 233 women with fibrocystic changes found that treatment with aqueous molecular iodine (I2) at a dose of 0.08 mg of I2/kg of body weight daily over 6 to 18 months was associated with improvement in pain and other symptoms in over 70% of participants (68). About 10% of the study participants reported side effects that were described by the investigators as minor. A double-blind, placebo-controlled trial of aqueous molecular iodine (0.07-0.09 mg of I2/kg of body weight daily for six months) in 56 women with fibrocystic changes found that 65% of the women taking molecular iodine reported improvement compared to 33% of those taking the placebo (68). A double-blind, placebo-controlled trial in 87 women with documented breast pain reported that molecular iodine (1.5, 3, or 6 mg/day) for six months improved overall pain (69). In this study, 38.5% of the women receiving 1.5 mg/day, 37.9% of those receiving 3 mg/day, and 51.7% of those receiving 6 mg/day reported at least a 50% reduction in self-assessed breast pain compared to 8.3% in the placebo group.
Large-scale, controlled clinical trials are needed to determine the therapeutic value of molecular iodine in fibrocystic breasts. Besides, the doses of iodine used in these studies (1.5 to 6 mg/day for a 60 kg person) are higher than the tolerable upper intake level (UL) recommended by the Food and Nutrition Board of the Institute of Medicine and should only be used under medical supervision (see Safety).