Structural Malformations in the Neonatal Rat Brain Accompany Developmental Exposure to Ammonium Perchlorate

Abstract: Environmental contaminants are often flagged as thyroid system disruptors due to their actions to reduce serum thyroxine (T4) in rodent models. The presence of a periventricular heterotopia (PVH), a brain malformation resulting from T4 insufficiency, has been described in response to T4 decrements induced by pharmaceuticals that reduce the hormone synthesis enzyme thyroperoxidase. In this report, we extend these observations to the environmental contaminant perchlorate, an agent that interferes with thyroid status by inhibiting iodine uptake into the thyroid gland. Pregnant rat dams were administered perchlorate in their drinking water (0, 30, 100, 300, 1000 ppm) from gestational day (GD) 6 until the weaning of pups on postnatal day (PN) 21. Serum T4 was reduced in dams and fetuses in late gestation and remained lower in lactating dams. Pup serum and brain T4, however, were not reduced beyond PN0, and small PVHs were evident in the brains of offspring when assessed on PN14. To emulate the developmental time window of the brain in humans, a second study was conducted in which pups from perchlorate-exposed dams were administered perchlorate orally from PN0 to PN6. This treatment reduced serum and brain T4 in the pup and resulted in large PVH. A third study extended the period of serum and brain TH suppression in pups by coupling maternal perchlorate exposure with maternal dietary iodine deficiency (ID). No PVHs were evident in the pups from ID dams, small PVHs were observed in the offspring of dams exposed to 300 ppm of perchlorate, and very large PVHs were present in the brains of pups born to dams receiving ID and perchlorate. These findings underscore the importance of the inclusion of serum hormone profiles in pregnant dams and fetuses in in vivo screens for thyroid-system-disrupting chemicals and indicate that chemical-induced decreases in fetal rat serum that resolve in the immediate postnatal period may still harbor considerable concern for neurodevelopment in humans

Impact/Purpose

 A wide variety of manmade chemicals have the potential to disrupt the thyroid axis act as thyroid system disrupting chemicals (TSDCs). Iodine is essential for production of the highly iodinated hormones of the thyroid gland. Perchlorate is an environmental contaminant that interferes with   iodine uptake into the thyroid gland, reducing thyroid hormone (TH) synthesis. As adequate supplies of TH are essential for brain development, exposures to perchlorate during pregnancy have raised concern for the developing brain. We have previously described a brain malformation, a heterotopia, resulting from inadequate supplies of thyroid hormone during critical period of brain development in a rodent model. To date these observations have been limited to the well known thyroid synthesis inhibitor, propylthiouracil, a drug used in the treatment of hyperthyroidism. In this paper we extend these observations to the environmental contaminant perchlorate. We show that restricted biological availability to perchlorate in the neonatal rat limits the magnitude of serum hormone reductions seen in the neonate and consequently the size of the brain malformation. However, when exposure conditions are created in the rodent model to parallel the critical period of thyroid hormone-dependent development in the human brain, very large malformation were induced. These observations have significant implications for the interpretation of regulatory studies of thyroid system disruption. Chemicals that reduce maternal thyroid hormones can limit hormone availability to the fetus and chemicals that reduce maternal thyroid hormones but also gain access to the fetal compartment threatening fetal hormone supplies present an additional risk to the developing brain. These findings underscore the importance of inclusion of serum hormone profiles in the pregnant dam and fetus in in vivo screens for thyroid system disrupting chemicals and indicate that chemical-induced decreases in fetal rat serum that resolve in the immediate postnatal period may still harbor considerable concern for neurodevelopment in humans.

Citation

Gilbert, M., Katherine O'Shaughnessy, K. Bell, AND J. Ford. Structural Malformations in the Neonatal Rat Brain Accompany Developmental Exposure to Ammonium Perchlorate. MDPI, Basel, SWITZERLAND, 11(12):1027, (2023). [DOI: 10.3390/toxics11121027]

DOI: Structural Malformations in the Neonatal Rat Brain Accompany Developmental Exposure to Ammonium Perchlorate