Issue 30 – More Thyroid

Why potential for chemicals to disrupt thyroid function is causing concern

Thyroid gland by Grays Anatomy, from Wikimedia

The thyroid gland. (Image: Grays Anatomy, Wikimedia.) Click to enlarge.

The Endocrine Society defines endocrine-disrupting chemicals as “compounds natural or synthetic which through environmental or inappropriate developmental exposures alter the hormonal and homeostatic systems that enable the organism to communicate with and respond to its environment.” Chemicals which affect thyroid metabolism are termed “thyroid disruptors”.

The thyroid system is complex. The main thyroid hormones are triiodothyronine (T3) and thyroxine (T4). They are synthesised by enzymes in the thyroid gland in response to thyroid-stimulating hormone, which is produced by the pituitary gland in response to instruction from the hypothalamus.  The synthesis requires iodide ions and is catalysed by hydrogen peroxide. The resulting hormones are stored in the body by transport proteins.

Interference at any of these points can potentially upset either the production of T3 and T4, or the balance of thyroid hormones in the body and in specific target cells and organs (such as the foetal brain). Even relatively minor fluctuations in thyroid hormone, of 25% within the normal range, can result in neurodevelopmental deficiencies in the foetus. Because of this, chemicals with the potential to disrupt thyroid function are increasingly a cause of concern.

A proportion of research into thyroid disruption treats levels of thyroid-stimulating hormone and serum total T4 (the amount of T4, both bound to transport proteins and free in the blood) as indicative of thyroid health. However, it is possible for T4 and TSH levels to be normal while other elements of the thyroid system are not working properly. This is important for research and risk assessment, because experiments which depend on measuring TSH and serum total T4 may therefore fail to observe thyroid disruption.

Laboratory research has shown a number of ways in which environmental chemicals can alter thyroid homeostasis without changing TSH levels. Four examples are:

  • The NIS receptor protein is crucial for concentrating iodine in the thyroid hormone-producing cells of the thyroid gland. Some chemicals can bind to this protein, resulting in lower iodine levels and inhibited synthesis of T3 and T4. Perchlorate can have this effect, and phthalates have been observed to have this effect in some animal studies.
  • T3 and T4 synthesis is aided by the enzyme TPO, which binds iodine to the tyrosine residues which ultimately become the hormone molecules. Several pesticides and fungicides have been found to inhibit the action of TPO, inhibiting the production of T3 and T4 by slowing down the rate at which the thyroid hormone building-blocks are manufactured in the cell.
  • TTR is one of three thyroid hormone transport proteins in the blood. By binding to T4, TTR creates a large pool of thyroid hormone in the blood which is available for release and uptake by cells in the body. If binding proteins are not available, free thyroid hormone is rapidly used up. A smaller reservoir of bound T4 could result in greater fluctuations in thyroid hormone levels.
  • Deiodinase enzymes pay an important role in local synthesis, activation and deactivation of thyroid hormones. Lead, chromium, UV-blocking agents and the pesticide methoxychlor have all been shown to interfere with the action of deiodinases, either increasing or decreasing local quantities of active thyroid hormone in e.g. the liver and the kidney.

Potential health consequences of thyroid disruption

In general, studies show subtle effects of environmental chemicals on thyroid hormone homeostasis but within normal reference values. Single chemicals have been observed to both suppress and elevate aspects of thyroid homeostasis. However, fluctuations within normal values in pregnant women and the foetus have been shown to have negative health consequences for the foetus, making healthy foetal development a major point of concern around thyroid disrupting chemicals.

Brain development: Although TTR binds to only about 20% of thyroid hormone in the blood (the binding protein TBG accounting for 75%), TTR is the major thyroid hormone transport molecule in the brain. For adult health, it is unlikely that enough T4 can be displaced from the TTR for acute toxic effects to be observed.

However, environmental chemicals which bind to the TTR could be transported across the blood/brain barrier into the foetal brain, decreasing foetal brain T4 levels. Even minor reductions in T4 can have permanent, harmful effects on brain development. PCBs, flame retardants and pentachlorophenol have been found to bind to TTR.

In the foetal brain, oligodendrocyte development and cell myelination are also under TH control. Both are essential for synaptogenesis, which is particularly rapid during foetal development. PCBs have mimicked the effect of hypothyroidism in rat pups, affecting brain development.

Thyroid auto-immune disease: There is not a great deal of research into thyroid auto-immune disease (TAD). US data suggests that 7-8% of the US population is affected, while diagnosis of TAD coincides with evidence of general autoimmune dysfunction, with detection of antibodies relating to vitiligo, alopecia, multiple sclerosis, lupus and other autoimmune disorders. Research has associated PCB exposure with TAD antibodies, suggesting a link between the two, though presence of antibodies does not mean that autoimmune pathology is manifested.

Cardiovascular system: T3 and T4 thyroid hormones are very important for development of the cardiovascular and nervous system. Changes in circulating T3 and T4 levels can result in impaired intellectual development in children, especially during the first trimester of pregnancy where even sub-clinical hypothyroidism has been observed to result in reduced IQ scores and other effects.

Summary of thyroid disruption mechanisms

  1. Inhibiting uptake of iodide through the cell membrane of thyrocyte cells, and therefore production of thyroxine in the thyroid gland, by blocking the NIS transporter
  2. Inhibiting synthesis of thyroid hormones by inhibiting the action of thyroperoxidase enzyme
  3. Binding in place of thyroid hormones to the TTR transport protein in the bloodstream
  4. Altering hepatic phase 2 catabolism by glucuronosyltransferase and sulfotransferase metabolism of T3 and T4, altering the levels of active hormone
  5. Altering metabolism of T4 by deiodinase enzymes
  6. Interfering with transport of thyroid hormones across cellular membranes blocking cellular receptors, in particular the TSH receptor.

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Chemicals known to alter thyroid homeostasis

Man-made chemicals which are relatively well-researched with regard to thyroid-disrupting effects are: PCBs, BPA, perchlorate, TCDD and PCDF (dioxins), pentachlorophenol (a breakdown product in the body of the pesticide hexachlorobenzene), triclosan and the PBDE flame retardants. Animal evidence of thyroid disruption exists for the phthalates DEHP, DnOP, DIDP, DNHP and DBP.

PCBs: Highly persistent, with 1.2 million tons manufactured and an estimated 0.4 million tons now in the environment. PCBs are no longer manufactured but found wide use in industrial coolant, paints, inks, plasticisers, flame retardants and caulking materials, among others. There have been few attempts at measuring levels of current exposure, though high levels have been found in US schools. They are ubiquitous in the environment and commonly found in people at varying levels.

PCBs and its hydroxylated metabolites bear particular structural similarity to T4. Studies of human exposure to PCBs and thyroid function suggest some PCB congeners can alter thyroid homeostasis. Higher concentrations of PCBs are associated with lower levels of circulating thyroid hormones. Findings are not entirely consistent, as exposure to PCBs has also been associated with higher levels of circulating thyroid hormones, while in others there is no change at all. Studies suggest that low-dose exposures have subtle effects on thyroid homeostasis, changing it but not predictably.

PBDE flame retardants: Banned in electronic goods in Europe, but still widely-present in furnishings meaning PBDE exposure is widespread, and potentially particularly high among toddlers because of their hand-to-mouth behaviours. Experiments on rodents have found that PBDE reduces circulating levels of THS. PBDE molecules with fewer bromine atoms seem to be more potent reducers of circulating T4. They are more structurally similar to T4 than PCBs.

In general, halogenated compounds seem to have stronger binding affinity to thyroid receptors than the parent compound. This may not be surprising, given the importance of iodine in the thyroid hormone molecule. Another brominated flame retardant, TBBPA, also bears significant structural similarity to T4. TBBPA is known to cross the human placental barrier, which suggests that it binds to transport proteins and could therefore cross the blood/brain barrier as well. However, there is little research into TBBPA’s effect on thyroid homeostasis.

Further reading:

Boas M, Feldt-Rasmussen U, Skakkebaek NE, Main KM. Environmental chemicals and thyroid function. Eur J Endocrinol. 2006 May;154(5):599-611. Review.

Boas M, Main KM, Feldt-Rasmussen U. Environmental chemicals and thyroid function: an update. Curr Opin Endocrinol Diabetes Obes. 2009 Oct;16(5):385-91. Review.

Patrick L. Thyroid disruption: mechanism and clinical implications in human health. Altern Med Rev. 2009 Dec;14(4):326-46. Review. Erratum in: Altern Med Rev. 2010 Apr;15(1):58.

Zoeller RT. Environmental chemicals impacting the thyroid: targets and consequences. Thyroid. 2007 Sep;17(9):811-7.

Zoeller RT, Rovet J. Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. J Neuroendocrinol. 2004 Oct;16(10):809-18.

Zoeller RT. Environmental chemicals targeting thyroid. Hormones (Athens). 2010 Jan-Mar;9(1):28-40.

5&5: News and science from August

News

Nine toxic chemicals join banned ‘dirty dozen’: Nine new chemicals have been formally added to the Stockholm Convention, an international treaty restricting use of POPs. Of particular interest is the addition of PFOAs, which are still widely used in non-stick and stain-resistant materials.

Chemical link to testicular cancer probed: The BBC reports on a new research technique which allows human foetal testicular development to be studied and therefore grant new insights into how chemicals affect reproductive development. This hasn’t been done before because it is clearly unethical to systematically expose foetuses to harmful chemicals and then harvest them to measure the effects.

Swedish government preparing a national ban on bisphenol A in baby bottles: The Swedish government has instructed the Swedish Chemicals Agency and the National Food Administration to propose how a national ban on bisphenol A in baby bottles and in certain plastic products could be designed.

Autism explosion half explained, half still a mystery: New Scientist reports on an interesting study which zeroes-out changes in diagnosis and awareness, to leave 50% of the rise in autism cases unexplained.

PCB threat lurks in Staten Island schools: A sobering reminder that if chemicals are used without adequate safety testing, they can be hard to get rid of – and can be found in some environments at startlingly high concentrations many years after being banned.

Science

Pulling Back the Curtain: Improving Reviews in Environmental Health: An explanation in EHP of an initiative to make it easier to come to a judgement about the meaning of a body of evidence in environmental health science, and how there is a need for a Cochrane-style “synthesis of the research through systematic and transparent reviews”.

Impact of Environmental Chemicals on Lung Development: The authors stress that “assessing effects of environmental chemicals on lung development requires end points not regularly included in standard toxicity tests.” This implies a need for significant change in how overall risk to health from chemical manufacture and use is calculated.

Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A: A new biomonitoring study appears to resoundingly refute toxicokinetic studies concluding that human exposure to unconjugated BPA is insignificant.

Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic: A new study finding a correlation between higher BPA levels and lower semen quality. The study is preliminary but does indicate that BPA’s influence on sperm quality should be an area for future research.

Signs of Puberty Seen Earlier in White Girls: The number of white girls developing signs of puberty at a younger age has almost doubled since the late 1990s, researchers have found.

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