Interactions of xenobiotics with thyroid hormone receptors and the effect on thyroid hormone levels

Brominated flame retardants are commonly used in a wide variety of products and processes, including plastics, paints, electronic parts and fabrics. Research is now revealing that contamination by several types of these compounds is extraordinarily widespread. Ilonka et al. observe that the chemical structures of some flame retardants is quite similar to the structure of thyroxine (T4), a human thyroid hormone. They conduct competitive binding experiments to measure the potency of brominated flame retardants to intefere with thyroid hormone function. Their results "indicate that brominated flame retardants, especially the brominated phenols and tetrabromobisphenol A, are very potent competitors for T4 binding to human transthyretin in vitro and may have effects on thyroid hormone homeostasis in vivo comparable to the thyroid-disrupting effects of PCBs." More...

Cheek, AO, K Kow, J Chen and JA McLachlan. 1999. Potential Mechanisms of Thyroid Disruption in Humans: Interaction of Organochlorine Compounds with Thyroid Receptor, Transthyretin, and Thyroid-binding Globulin Environmental Health Perspectives 107: 273-278

Organochlorine compounds are well known to alter the thyroid hormone system by decreasing serum thyroid hormone levels in several species including humans. Cheek et al. examine the ability of PCBs, DDT and its metabolites, and several organochlorine pesticides (acetochlor, alachlor and methoprene) to bind to human thyroid hormone receptors and thyroid hormone transport proteins. Hydroxylated organochlorine have a high affinity to thyroid transport proteins, but their affinity to thyroid receptors was unknown prior to this study. Out of all the compounds, only hydroxylated PCBs bound to the human thyroid receptor, but had a greater binding affinity to the thyroid transport protein, transthyretin. These findings help to narrow the scope of the investigation into the mechanism by which organochlorine compounds alter the thyroid hormone system.

Osius, N, W Karmaus, H Kruse and J Witten. 1999. Exposure to Polychlorinated Biphenyls and Levels of Thyroid Hormones in Children Environmental Health Perspectives 107(10) October

Osius et al. present findings on the impact of living near a toxic incineration plant with license to burn PCB contaminated material on thyroid hormone levels in children. The study reports a significant positive association between the PCB congener 118 and thyroid stimulating hormone, and a significant negative correlation between five PCB congeners (138, 153, 180, 183 and 187) to the thyroid hormone, triiodothyronine (unbound to a protein) in children between 7-9 years of age. This thyroid hormone makes up about 9% of the thyroid hormones secreted from the thyroid. The study found no significant correlation with PCB and thyroxine, which accounts for 90% of the thyroid hormones. However, they did report an association between cadmium and increasing levels of thyroid stimulating hormone and decreasing levels of thyroxine.

The authors examined two areas north and southeast of the region in immediate proximity to the incinerator for comparison. The levels of both thyroxine and triiodothryonine were significantly decreased in the incinerator region, as compared with the two other regions.

In an ambitious review of the literature from laboratory experiments, wildlife observations and human epidemiology, Françoise Brucker-Davis concludes that wildlife data clearly demonstrate thyroid disruption by synthetic chemicals. Studies of fetal exposure to contaminants known to be thyroid disruptors in humans demonstrate impacts also, particularly with respect to subsequent cognitive function in childhood, but the mechanisms of action are not clear. More...

Thyroid hormones play important roles in growth and reproductive capacity in reptiles. Removal of the thyroid in lizards and geckos can result in the inhibition of spermatogenesis that can be restored with the administration of thyroxine. Exposing geckos with an intact thyroid to triiodothyronine also results in the suppression of spermatogenesis, suggesting that the normal functioning of reproductive organs is dependent on a specific range of thyroid hormone levels.

Crain et al. examine sex steroid and thyroid hormone levels in juvenile alligators of three lakes in Florida. Two of the lakes are highly contaminated; Lake Apopka experienced a chemical spill in 1980, and the other, Lake Okeechobee has a combination of chemical sources, but has had no major spill. The third lake, Lake Woodruff, is used as a reference lake.

Plasma levels of thyroxine and triiodothyronine were examined, as well as the relationship of the thyroid hormones to alligator size. The concentrations of thyroid hormones in alligators differed in all three lakes. Thyroxine levels were elevated in Lake Okeechobee compared to the reference lake. In the reference lake, thyroid hormone levels had a strong negative correlation to alligator size. Thyroxine levels in the males of the contaminated lakes were negatively correlated to size, but there was no clear relationship in the females. Triiodothyronine levels of the females in Lake Apopka had a negative relationship to size, but there was no correlation in the males of either contaminated lake to triiodothyronine.

These results clearly indicate the alteration of the thyroid hormone system in alligators living in contaminated lakes. There are two significant questions that emerge from this study; first, if thyroid hormone levels are abnormal during a juvenile state is this an indication of embryonic exposure and is, therefore, a permanent alteration; and second, will the alteration of thyroids have a significant impact of the reproductive potential of this cohort of alligators?

Leatherland et al. conduct a comparative review of studies on experimental mice and rats exposed to environmental contaminants via a diet of contaminated fish from the Great Lakes, or through direct exposure to PCB mixtures or polyhalogenated aromatic hydrocarbons (PHAHs), and the subsequent impact on the thyroid hormone system. They report that the thyroid responses of experimental rats and mice fed the PHAHs were similar to those of rats and mice fed contaminated fish from the Great Lakes.

This finding is significant because the thyroid responses of the experimental animals fed contaminated fish were at exposure levels of mixed PHAHs "several orders of magnitude lower than those applied in the classical toxicology studies." Moreover, because Great Lakes fish are contaminated with a combination of compounds, the impact on the thyroid hormone system may be due to some synergistic mechanisms.

SP Porterfield and CE Hendrich. 1993. The Role of Thyroid Hormones in Prenatal and Neonatal Neurological Development-Current Perspectives Endocrine Reviews 14(1): 94-106

SP Porterfield and SA Stein. 1994. Thyroid Hormones and Neurological Development: Update 1994 Endocrine Reviews 3(1):357-363

These comprehensive reviews by Susan P. Porterfield examine the role of thyroid hormones on normal brain development, and the impact of thyroid hormone abnormalities on the fetal brain.

The critical period for thyroid hormones in brain development occurs in humans in late gestation to 1-2 years of age (in rats this period is equivalent to 18 days of gestation to 21 days neonatal). Thyroid deficiency (hypothyroidism) at birth has several implications on the brain and middle ear development. Too much or too little of these hormones can result in the decrease of cells in the mature brain, can impair neurological development and can alter middle ear development. Untreated congenital hypothyroidism will result in severe mental retardation and hearing loss. Subtle effects of treated congenital hypothyroidism include learning disabilities, speech and memory problems, and poor coordination and balance. Similar behavioral and neurological problems emerge in children whose mothers had thyroid hormone deficiency or hyothyroxinemia during pregnancy.

McKinney JD, Pedersen LG 1987. Do residue levels of polychlorinated biphenyls (PCBs) in human blood produce mild hypothyroidism? Journal of Theoretical Biology 129(2):231-41.

PCBs are nearly ubiquitous environmental contaminants, occurring in most human adipose tissue and blood samples. It has recently been recognized that PCBs and related compounds share important structural properties with thyroid hormones and can bind thyroid hormone binding proteins. It is reasonable that such specific binding interactions can modulate the distribution of these compounds in the body and alter hormone-protein interactions that are responsible for the maintenance of normal thyroid status. Most of the available evidence indicates that the levels of free thyroid hormones in plasma are a reflection of the maintenance of normal thyroid status in any individual. A theoretical model for the transport of thyroid hormones in blood has been extended to estimate the modulating effects of PCBs on free thyroid hormones. Using conservative assumptions based on experimental data, our calculations indicate that PCB concentrations normally found in humans can effect significant increases in free thyroxine levels in serum by competing with serum thyroid hormone binding proteins. Experimental data are discussed which support the proposal that antagonist binding of PCBs to thyroid hormone binding proteins in serum could produce varying degrees of hypothyroidism. The biological result is compatible with the "equilibrium hypothesis" in which thyroid hormone redistributes between specific and nonspecific binding proteins rather than emphasizing the importance of free hormone as the active moiety.

Talk to us: email