Parvalbumin as a Target for Thyroid Hormone Mediated Developmental Neurotoxicity
On this page:
Thyroid hormones (TH) are critical for neurodevelopment. Parvalbumin (Pvalb), a calcium binding protein in a large population of cortical inhibitory interneurons has been shown in mutant mouse models to be sensitive to TH disruption. Pvalb-expressing interneurons are critical to neural network formation and disruption during brain development has been linked to neurodevelopmental disorders. To determine if Pvalb-expression is altered by moderate TH perturbations, we exposed pregnant rats to low doses of a known TH-synthesis disruptor, propylthiouracil (PTU, 0, 0.5, 1, 3ppm in drinking water). We aimed to characterize, quantitatively, Pvalb-expression in different brain regions using proteomic and immunohistochemical (IHC) techniques and determine the utility of these approaches for the detection of TH-dependent neurotoxicity. Dams were exposed throughout gestation and lactation and blood and brains were collected from offspring on postnatal day (PN) 14 and PN22 (2 males/litter/dose/age). One brain at each age was immersion fixed for Pvalb IHC, the other was dissected, the anterior cortex removed, flash-frozen, and prepared for targeted proteomics of Pvalb using LC-MS/MS. Clear age-dependent increases in Pvalb-expression were noted by IHC, with a reduction in Pvalb-expression notable in all treatment groups at both ages relative to controls (n=2/dose group). Targeted proteomics proved to be less sensitive at PN14, however at PN22 concentrations of Pvalb were measurable showing a dose dependent Pvalb protein reduction in the 1 and 3ppm groups compared to controls (n=6-8/dose group). These findings extend previous observations of TH-dependent neurotoxicity to milder levels of TH insufficiency, revealing negative impacts on this critical neuronal population. Does not reflect EPA policy.