Thyroid Hormone System Adverse Outcome Pathways and Developmental Neurotoxicity
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The Adverse Outcome Pathway (AOP) framework has been adopted as means to assemble, organize, and integrate all available biological information to support sound regulatory decision making. Environmental chemicals can interfere with the thyroid system at numerous sites, and these are most often detected by alterations in circulating levels of thyroid hormone. There is significant public health need to provide protection of the developing brain of the fetus, newborn, and young child from thyroid system disrupting chemicals. The AOP provides a scientific grounding to link alterations in serum hormone to downstream events that underlie thyroid-mediated neurodevelopmental impairments. In this presentation the effects of developmental exposure to perchlorate and iodine deficiency will be examined within the context of AOP. Previous studies revealed dose-dependent alterations in hippocampal synaptic transmission with exposure to perchlorate or under conditions of iodine deficiency, but with no effect on behavioral measures of cognitive function. In this report combined exposure to perchlorate under conditions of dietary iodine deficiency revealed structural defects in brain and deficits in behavioral measures of sensory gating. Reductions in serum and brain hormones in the fetus that persist to the first week of life were required to induce morphological changes in brain. Neurodevelopmental effects of perchlorate exposure are not only unmasked but greatly exacerbated under conditions of dietary iodine insufficiency, effects that would not necessarily be predicted from rodent models of either one alone.