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Certain polyhalogenated aromatic hydrocarbons such as polychlorinated biphenyls (PCBs) and dibenzo-p-dioxins (dioxins, 2,3,7,8-tetrachlorodibenzo-p-dioxin) have been shown to have neurotoxic effects and to alter thyroid function during critical periods of thyroid hormone-dependent brain development. This has led to the suggestion that some of the neurotoxic effects of these compounds could be mediated through the thyroid system. Thyroid hormones are essential for normal brain development during a critical period beginning in utero and extending through the first 2 years postpartum. They regulate neuronal proliferation, migration, and differentiation in discrete regions of the brain during definitive time periods. Even transient disruption of this normal pattern can impair brain development. Thyroid hormones are necessary for normal cytoskeletal assembly and stability and the cytoskeletal system is essential for migration and neuronal outgrowth. In addition, they regulate development of cholinergic and dopaminergic systems serving the cerebral cortex and hippocampus. Animals perinatally exposed to certain environmental organohalogens such as many of the PCBs and dioxins have abnormal thyroid function and neurologic impairment. Although there are both species and congener variabilities, most reports show exposure results in thyroid enlargement and reduced serum T4 levels with normal T3 levels. Initial research concentrated on studying the direct actions of xenobiotics on the thyroid; however, some of these compounds bear a structural resemblance to the natural thyroid hormones and have high affinity with thyroid hormone-binding proteins such as transthyretin. These compounds could act as agonists or antagonists for receptors of the thyroid/steroid/retinoic acid superfamily. These structurally similar organohalogens could act at multiple points to alter thyroid hormone action. The similarity of the neurologic impairment seen in thyroid disorders to that seen following PCB or dioxin exposure suggests that one mechanism of neurotoxicity of these compounds could involve interaction with the thyroid system.

Neurologic development follows orderly patterns that can be severely disturbed when thyroid hormones are deficient or excessive. Should this occur at appropriate development periods, irreversible neurologic damage can result. The nature of the deficits depends upon the specific development period and the severity of the thyroid disturbance. PCBs and dioxins are structurally similar to the thyroid hormones. Their binding characteristics are similar to those of thyroid hormones and all three groups bind to the cytosolic Ah receptor, the thyroid hormone receptor and the serum thryoid hormone binding protein transthyretin. Depending upon the dose of toxin and the congener used, the toxins either decrease or minic the biological action of the thyroid hormones. Either effect, if occurring during brain development, can have disastrous consequences. Children and animals exposed to PCBs or dioxins in utero and/or as infants can exhibit varying degrees of behavioral disorders. These disorders resemble those seen in children exposed to thyroid hormone deficiencies in utero and/or in infancy. The mechanism of developmental neurotoxicity of PCBs and dioxins is not known but data suggest it could be partially or entirely mediated by alterations in availability and action of thyroid hormones during neurological development. It is possible that transient exposure of the mother to doses of toxins presently considered nontoxic to the mother could have an impact upon fetal or perinatal neurological development. If the toxins act via their effect on thyroid hormone action, it is possible that doses of toxins that would normally not alter fetal development, could become deleterious if superimposed on a pre-existing maternal/or fetal thyroid disorder. Environ Health Perspect 102(Suppl 2): 125-130 (1994).

Thyroid hormones regulate neuronal proliferation, migration, process outgrowth, synaptic development, and myelin formation in specific brain regions. Because brain development occurs during discrete windows of time, inappropriate levels of thyroid hormones in definitive periods can produce permanent damage, the nature of which depends upon the timing and magnitude of the insult. Thyroid hormones cross the placenta and enter the brain primarily as thyroxine (T4); therefore, conditions selectively lowering serum T4 levels alter brain hormone availability. Triiodothyronine (T3) is the predominant form of the hormone that binds to the receptor. T3 is produced from T4 in the brain by the enzyme type II, 5'-deiodinase. Polychlorinated biphenyls (PCBs) are synthetic environmental toxicants that bear a striking structural resemblance to the active thyroid hormones and can, depending upon the species, dosage, and congener used, act as agonists, antagonists, and partial agonists to thyroid hormones.

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