Relevance of Biomarkers of Effect in the Detection of Thyroid Disrupting Chemicals
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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, 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 differetial gene expression and abnormal cell migration is a reproducible effect. In this presentation we first show how gene expression assays correlate to developmental nuerotoxicity following exposure to several chemicals including environmental contaminants. We next examined if targeted histopathology assays could also be used in a regulatory context. We leveraged our putative AOP (AOP 402) 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 both gene expression and histopathology are predictive of developmental neurotoxicity, and correlate to adverse outcomes better than serum T4 alone. This work suggests that these proposed targeted testing strategies in the developing rat brain can strengthen the interpretation of serum T4 measures, thus improving chemical assessment.