Iodine Deficiency Exacerbates Thyroidal and Neurological Effects Of Developmental Perchlorate Exposure in the Neonatal and Adult Rat

Abstract: Thyroid hormones (THs) require iodine for biosynthesis and play critical roles in brain development. Perchlorate is an environmental contaminant that reduces serum THs by blocking the uptake of iodine from the blood to the thyroid gland. Using a pregnant rodent model, we examined the impact of maternal exposure to perchlorate under conditions of dietary iodine deficiency (ID) on the brain and behavior of offspring. We observed modest reductions in thyroxine (T4) in the serum of dams and no effect on T4 in pup serum in response to maternal exposure to 300 ppm of perchlorate in the drinking water. Likewise, serum T4 was reduced in ID dams, but, as with perchlorate, no effects were evident in the pup. However, when ID was coupled with perchlorate, reductions in pup serum THs and transcriptional alterations in the thyroid gland and pup brain were detected. These observations were accompanied by reductions in the number of cortical inhibitory interneurons containing the calcium-binding protein parvalbumin (Pvalb). Alterations in Pvalb expression in the neonatal brain were associated with deficits in the prepulse inhibition of acoustic startle in adult male offspring and enhanced fear conditioning in females. These findings support and extend structural defects in the brain previously reported in this model. Further, they underscore the critical need to consider additional non-chemical stressors in the determination of hazards and risks posed by environmental contaminants that affect the thyroid system.

Impact/Purpose

Neurodevelopmental disorders arise due to changes in developmental trajectories of neurons during the early stages of circuit assembly in the brain. Thyroid hormones (TH) play a critical role in orchestrating the timing of those trajectories. Iodine is a fundamental element required for TH synthesis. Iodine deficiency is a global problem having substantial implications during pregnancy when demands for TH increase dramatically to meet fetal and maternal needs.  A wide variety of manmade chemicals have the potential to disrupt the thyroid axis act as thyroid system disrupting chemicals (TSDCs). In a rodent model, we have previously described the inductions of a structural brain malformation, a heterotopia, induced by exposure to the TSDC, ammonium perchlorate, an environmental contaminant found in food and drinking water supplies in this country.  The magnitude and severity of this malformation was greatly exacerbated under conditions of marginal iodine deficiency. In this report, we extend these observations to another structural defect in the developing brain, a reduction in the number of a specific set of inhibitory interneurons essential for the proper networking of neural circuitry in the developing brain. Perturbation of the thyroid axis and the emergence of these structural defects were only revealed when perchlorate was delivered to iodine deficient dams. Deficits in a behavioral model of schizophrenia, a neurodevelopmental disorder tied to disruption of inhibitory circuitry, were also revealed in adult offspring of affected dams. These findings underscore the critical need to consider additional non-chemical stressors in the determination of hazards and risks posed by environmental contaminants that affect the thyroid system.

Citation

Gilbert, M., M. Hawks, K. Bell, W. Oshiro, C. Wood, BJ George, Ryno Thomas, AND J. Ford. Iodine Deficiency Exacerbates Thyroidal and Neurological Effects Of Developmental Perchlorate Exposure in the Neonatal and Adult Rat. MDPI, Basel, SWITZERLAND, 12(12):842, (2024). [DOI: 10.3390/toxics12120842]

DOI: Iodine Deficiency Exacerbates Thyroidal and Neurological Effects Of Developmental Perchlorate Exposure in the Neonatal and Adult Rat