The Cellular Effects of Thyroid Disrupting Chemicals in the Rat Brain
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Various environmental contaminants can reduce thyroid hormones (THs) in laboratory animals and are correlated to thyroid disease in some populations. One of the primary concerns of these contaminants is their impact on neurodevelopment, as THs are required for normal brain patterning and function. As such, some standardized developmental and reproductive toxicity studies suggest or require serum thyroxine (T4) measures in rat dams and their offspring. However, since the developing brain is not often examined concurrently by either histopathology or neurobehavior, it is unclear what degree of T4 reduction is adverse. To address this data gap, we characterized the mechanistic underpinnings of how hypothyroidism affects neurodevelopment in the rat, showing that abnormal cell migration is a reproducible effect. We next leveraged this knowledge to interpret how a perfluoroalkyl substance, perfluorohexanesulfonate (PFHxS), may affect both the thyroid system and the brain in postnatal rats. We show that a maternal exposure to either 17 or 50 mg/kg PFHxS across gestation and lactation reduces serum T4 in both the exposed dam and in their pups as compared to controls. Surprisingly, brain T4 in neonates was largely unaffected by PFHxS, and our immunochemical markers of thyroid dysfunction in the brain appeared normal. This includes a typical appearance of radial glial cells, neural progenitors that mediate cell migration, and no evidence of a phenotype indicative of abnormal migration (periventricular heterotopia). Together, these data show that despite a serum T4 reduction in PFHxS exposed pups, the brain is likely not affected by a TH deficit during this period. This work suggests that directed evaluation of cell migration in the developing rat brain can strengthen the interpretation of serum T4 measures, thus improving chemical assessment. This work does not reflect US EPA policy.