Biomarkers of Neurodevelopmental Effect Are Necessary to Interpret Chemical Action In Vivo
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2022 SOT Symposium
Speaker 5: Katherine O’Shaughnessy
Biomarkers of Neurodevelopmental Effect Are Necessary to Interpret Chemical Action In Vivo
One of the primary concerns of thyroid disrupting chemicals is their potential impact on neurodevelopment, as thyroid hormones control normal brain patterning and function. As such, some standardized developmental and reproductive toxicity studies suggest or require serum T4 measures in rats. However, the developing brain is not often examined concurrently, so it is unclear if/when a serum T4 deficit is adverse. To address this data gap, we have been characterizing mechanisms of thyroid-dependent neurotoxicity in rats and have identified several potential biomarkers of neurotoxicity. In this seminar this basic science work is discussed, and then presented in the context of a perfluoroalkyl substance, perfluorohexanesulfonate (PFHxS). PFHxS purportedly reduces serum T4 by multiple mechanisms in vivo, although its neurotoxic potential is unclear. We show that a maternal exposure to PFHxS reduces serum T4 in both the exposed dam and in their pups as compared to controls. Surprisingly, brain T4 and T3 in neonates was largely unaffected, and our immunochemical markers of thyroid dysfunction in the neonatal brain appeared normal. This includes a typical appearance of neural progenitors that mediate cell migration and no evidence of one adverse outcome assayed. However, RNA-Sequencing (RNA-Seq) of the developing liver and brain suggests that PFHxS has multiple mechanisms of action in vivo, and the brain may still be affected by a thyroid dysregulation. This work shows that environmental contaminants have complex biological effects and demonstrates how molecular biomarkers may improve chemical assessment. This work does not reflect US EPA policy.