Several classes of environmental contaminants have been claimed or suggested to possess endocrine-disrupting potency, which may result in reproductive problems and developmental disorders. In this paper the focus is on the multiple and interactive mechanisms of interference of persistent polyhalogenated aromatic hydrocarbons (PHAHs) and their metabolites with the thyroid hormone system. Evidence suggests that pure congeners or mixtures of PHAHs directly interfere with the thyroid gland; with thyroid hormone metabolizing enzymes, such as uridine-diphosphate-glucuronyl transferases (UGTs), iodothyronine deiodinases (IDs), and sulfotransferases (SULTs) in liver and brain; and with the plasma transport system of thyroid hormones in experimental animals and their offspring. Changes in thyroid hormone levels in conjunction with high PHAH exposure was also observed in captive as well as free ranging wildlife species and in humans. Maternal exposure to PHAHs during pregnancy resulted in a considerable fetal transfer of hydroxylated PHAHs, which are known to compete with thyroxine (T4) for plasma transthyretin (TTR) binding sites, and thus may be transported to the fetus with those carrier proteins that normally mediate the delivery of T4 to the fetus. Concomitant changes in thyroid hormone concentrations in plasma and in brain tissue were observed in fetal and neonatal stages of development, when sufficient thyroid hormone levels are essential for normal brain development. Alterations in structural and functional neurochemical parameters, such as glial fibrillary acidic protein (GFAP), synaptophysin, calcineurin, and serotonergic neurotransmitters, were observed in the same offspring up to postnatal day 90. In addition, some changes in locomotor and cognitive indices of behavior were observed in rat offspring, following in utero and lactational exposure to PHAHs. Alterations in thyroid hormone levels and subtle changes in neurobehavioral performance were also observed in human infants exposed in utero and through lactation to relatively high levels of PHAHs. Overall these studies indicate that persistent PHAHs can disrupt the thyroid hormone system at a multitude of interaction sites, which may have a profound impact on normal brain development in experimental animals, wildlife species, and human infants.

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The majority of the known transthyretin (TTR) variants are associated with amyloidosis, but there are also variants associated with euthyroid hyperthyroxinemia and others are apparently nonpathogenic. TTR Met 119 is a nonpathogenic variant found to be frequent in the Portuguese population. Previous studies on thyroxine (T4) binding to semi-purified TTR from heterozygotic carriers of TTR Met 119, reported by us and other groups, revealed different results. Therefore, to further characterize T4 binding to TTR Met 119 we performed T4-TTR binding studies in homotetrameric-recombinant TTR Met 119 variant and normal TTR. We also studied T4 binding to TTR purified from serum of different heterozygotic carriers of TTR Met 119 including compound heterozygotic individuals carriers of a TTR mutation in the other allele. We observed an increased T4 binding affinity to TTR Met 119 from heterozygotic individuals and compound heterozygotes and this effect of increasing T4 binding affinity was consistent and independent from the mutation present in the other allele. Recombinant homotetrameric TTR Met 119 and heterotetrameric protein from heterozygotic carriers of TTR Met 119 presented similar T4 binding affinity demonstrating the increased T4 binding affinity of TTR Met 119. X-ray crystallography studies performed on the recombinant TTR Met 119 variant revealed structural alterations mainly at the level of residue Leu 110 allowing a closer contact between the hormone and the mutant protein. These results are consistent with the observed T4 binding results.

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