Ammonium Perchlorate: Serum Dosimetry, Neurotoxicity and Resilience of the Neonatal Rat Thyroid System

The environmental contaminant perchlorate impairs the synthesis of thyroid hormones by reducing iodine uptake into the thyroid gland. Despite this known action, moderate doses of perchlorate do not significantly alter serum thyroid hormone in rat pups born to exposed dams. We examined perchlorate dosimetry and responsivity of the thyroid gland and brain in offspring following maternal exposure to perchlorate. Pregnant rat dams were delivered perchlorate in drinking water (0, 30, 100, 300, 1000 ppm) from gestational day 6 to postnatal day (PN) 21. Perchlorate was present in the placenta, milk, and serum, the latter declining in pups over the course of lactation. Serum and brain thyroid hormone were reduced in pups at birth but recovered to control levels by PN2. Dramatic upregulation of Nis was observed in the thyroid gland of the exposed pup. Despite the return of serum thyroid hormone to control levels by PN2, expression of several TH-responsive genes was altered in the PN14 pup brain. Contextual fear learning was unimpaired in the adults, supporting previous reports. Declining levels of serum perchlorate and a profound upregulation of Nis gene expression in the thyroid gland are consistent with the rapid return to the euthyroid state in the neonate. However, despite this recovery, thyroid hormone insufficiencies in serum and brain beginning in utero and present at birth appear sufficient to alter TH action in the fetus and subsequent trajectory of brain development. Biomarkers of that altered trajectory remain in the brain of the neonate, demonstrating that perchlorate is not devoid of effects on the developing brain.

Impact/Purpose

    A wide variety of manmade chemicals have the potential to disrupt the thyroid axis act as thyroid system disrupting chemicals (TSDCs). The thyroid system is complex and presents many targets for chemical interaction. Implementation of novel in vitro screens have identified chemical that interact with several of these target sites, one of them being the sodium-iodine symporter, or NIS. 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. This paper describes the effects of exposure of pregnant rat dams to a classic chemical NIS inhibitor, perchlorate, on serum, thyroid gland and brain in the dam and pup, expanding on our previous work in the developing fetal brain.    The goals of this study were 1) to extend our previous work defining dose-response profiles of TH in the maternal and fetal compartments of pregnant rats to include postnatal period in response to a NIS inhibition by perchlorate, 2)  extend observations of peripheral effects in serum and thyroid gland and fetal brain to the postnatal period, and 3) to support development of a quantitative Adverse Outcome Pathway (AOP) and physiologically based dose response (PBPK) models for NIS-related TH disruption. Perchlorate was delivered to rat dams via drinking water from gestational day 6 to postnatal day 21.  Maternal TH in the thyroid gland and serum were dose-dependently reduced, steeper declines were observed in the newborn pup. TH were also reduced in the newborn pup brain, but both serum and brain hormones quickly recovered by PN2 despite continued maternal exposure.  Gene expression changes in the gland revealed dramatic increases in expression of Nis, serum perchlorate concentrations fell, and large increases in serum TSH were evident. Combined, these events contributed to rapid recovery of serum markers in the early postnatal period. Despite full recovery of serum and brain hormones, significant reductions in a number of molecular markers of TH-action remained in the cortex and hippocampus of the PN14 pup brain.    The findings expand empirical observations to these downstream biological substrates of TSDC. They underscore the importance of incorporating fetal or newborn thyroid hormone measures in an examination of TSDCs and the utility of the EPA’s ‘Comparative Thyroid Assay’ (CTA) for regulatory purposes. The timing of birth relative to developmental trajectories in brain complicate the extrapolation of findings of TSDCs from rodents to humans. Both species are highly dependent on appropriate supplies of thyroid hormone for a variety of neurodevelopmental processes. In the rat, many of these processes begin in late gestation and extend into the first few weeks of neonatal life. In humans, these parallel developmental programs largely occur in utero. If, as shown here in the rat, perchlorate is readily transferred across the placenta from a pregnant woman to her fetus, thyroid hormone disruption induced by NIS inhibition of the fetal thyroid gland is likely to ensue and persist during the critical phases of thyroid-hormone dependent neurodevelopment in humans. In the rodent model, the impaired thyroid status established by perchlorate in the fetus is not sustained throughout the critical periods of postnatal brain development, reducing the impact of this exposure on neurodevelopment. This will not be the case in humans where these processes occur prenatally. Despite the more limited impact of perchlorate exposure on serum and brain hormones, molecular markers of altered thyroid hormone action persisted.

Citation

Gilbert, M., I. Hassan, Katherine O'Shaughnessy, C. Wood, T. Stoker, C. Riutta, AND J. Ford. Ammonium Perchlorate: Serum Dosimetry, Neurotoxicity and Resilience of the Neonatal Rat Thyroid System. Society of Toxicology, RESTON, VA, 198(1):113-127, (2023). [DOI: 10.1093/toxsci/kfad133]

DOI: Ammonium Perchlorate: Serum Dosimetry, Neurotoxicity and Resilience of the Neonatal Rat Thyroid System