PFHxS and Developmental Neurotoxicity: Does Thyroid Hormone Action Play a Role?
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Perfluorohexane sulfonate (PFHxS) is an environmental thyroid disrupting chemical that reduces serum thyroid hormones (THs) in animal models. As thyroid action is required for normal brain development, it is suspected that PFHxS may induce developmental neurotoxicity by endocrine mediated mechanisms. Using a multidisciplinary approach, we investigate whether PFHxS induces abnormal brain development and function associated with TH dysregulation. Pregnant rats were orally dosed (50 mg/kg/day) from gestational day 6 (GD6) to postnatal day 21 (PN21), permitted to give birth, and the offspring analyzed. Results show that PFHxS exposure reduced serum THs in both the dams and pups. Serum total thyroxine (T4) was reduced by approximately 75% in exposed neonates. However remarkably, brain T4 was only significantly reduced in the pup brain on PN0, and not on PN2, PN6, or PN14. Brain triiodothyronine (T3) was also not significantly reduced at any stage tested. We also detected no evidence, transcriptionally or phenotypically, of TH-mediated dysfunction of the cortex. No significant differences in learning and memory were detected in offspring aged to adulthood, as assayed by trace fear conditioning; sensory gating was similarly unaffected. These data suggest that despite significant reductions in serum T4, the neonatal rat brain does not appear to be TH insufficient following PFHxS exposure. These observations may be attributed to chemical action: PFHxS purportedly reduces serum THs by interfering with the function of serum binding proteins. However, unbound (free) THs are transported across the blood brain barrier and into the tissue. Thus, these dynamics in hormone transport may explain why brain TH concentrations are largely unaffected by PFHxS exposure at the stages tested. This hypothesis is consistent with clinical presentations of patients and knockout mice possessing loss of function mutations in serum binding proteins. In the future additional work is warranted to determine if other perfluorinated compounds alter brain TH concentrations at other developmental stages, and/or induce abnormal brain development by other mechanisms. This work does not reflect EPA policy.