Citation:

Bell, K., C. Riutta, G. Jung, J. McCord, J. Ford, S. Thomas, C. Wood, W. Oshiro, Mary E. Gilbert, AND K. OShaughnessy. Perfluorohexane sulfonate (PFHxS) Induces Maternal Hypothyroxinemia but Does not Result in Developmental Neurotoxicity by a Thyroid-Mediated Mechanism. Birth Defects Research and Prevention Society and the Developmental Neurotoxicology Society Meetings (held concurrently) - Presented virtually, Charleston, South Carolina, June 29, 2020.

Impact/Purpose:

Thyroid hormones (TH) are critical for brain development. Many per- and polyfluoroalkyl substances (PFAS) are known to reduce serum THs in rats, and exposure to various PFAS are also associated with thyroid disorders in some human populations. Furthermore, the published literature has shown that some PFAS can induce developmental neurotoxicity in animals, though the precise mechanism is unknown. This abstract examines how the contaminant perfluorohexane sulfonic acid (PFHxS) affects thyroid function in rat mothers and offspring. Rat offspring born to PFHxS exposed mothers were then evaluated for known indices of developmental neurotoxicity (structural and functional phenotypes), that are resultant from aberrant thyroid hormone action. The multidisciplinary approach employed in this study is a fundamental step in characterizing if, and how, PFHxS induces abnormal brain development.

Description:

Perfluorohexane sulfonate (PFHxS) is a ubiquitous environmental contaminant that can be quantified in the sera of infants, childrens, and adults throughout the United States. With regards to health effects, epidemiology studies have correlated PFHxS exposure to thyroid dysfunction in some populations. These human data suggest that pregnant women and children may be an important at-risk demographic, as normal thyroid hormone action (TH) is critical for neurodevelopment in children. To determine if PFHxS alters TH action and brain development during the perinatal period, pregnant Long Evans rats were orally dosed with 0, 17, or 50 mg/kg/day of PFHxS from gestational day (GD) 2 to postnatal day (PN) 14, and the dams and offspring were evaluated. In the dam, exposure to 17 or 50 mg/kg PFHxS reduced serum total thyroxine (T4) by 40% and 48% respectively; however, no significant increases in thyroid stimulating hormone were observed. In the PFHxS exposed neonates, serum total thyroxine (T4) was reduced between 45% and 80% on PN0, PN2, and PN6 as compared to controls. Serum total triiodothyronine (T3) was also reduced at these same stages, though by smaller magnitudes (12-26%). However interestingly, brain T4 was only marginally reduced by 25% in newborn (PN0) animals exposed to 50/mg/kg PFHxS; no differences in brain T3 were detected on PN0, 2, 6, or 14. In support of these data, gene expression analyses of a brain region sensitive to TH action on PN6 did not reveal a transcriptional signature reminiscent of TH insufficiency. We also did not detect any morphological (periventricular heterotopia) or functional phenotypes (learning/memory and sensory gating) consistent with developmental hypothyroidism. These data suggest that despite maternal hypothyroxinemia, the developing brain does not appear to be affected by abnormal thyroid action. However, our gene expression analyses revealed significant decreases in two transcription factors that control neural stem cell function (SRY-Box 2 and Paired box 6), suggesting that PFHxS may affect brain development by a chemical-specific mechanism. This work does not reflect US EPA policy.

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