Developmental Exposure to Flame Retardant Toxicants (PBDEs) Produces Autistic-Like Reprogramming of Behavior and Hypothalamic Oxytocin in a Thyroid- and Sex-Dependent Manner

Abstract

Introduction: The prevalence of psychosocial neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) is rising at an alarming rate. ASD etiology is multifactorial, resulting from sex-specific genetic susceptibilities that may interact with environmental toxicant exposures during critical developmental periods. In humans, PBDEs are thyroid-disrupting chemicals associated with altered socioemotional behavior, decreased IQ and hyperactivity. We have previously demonstrated autistic-like effects produced by perinatal exposure to PBDEs in female mice (Kozlova et al, 2022; PMID: 34687351). Maternal thyroid hormone (TH) status affects fetal brain development and has been linked to ASD. Since thyroid hormones regulate oxytocin (OXT) and/or vasopressin neuroendocrine systems critical for social behavior, PBDEs may produce autistic-like actions via disruption of the thyroid system. Therefore, this study tested the hypothesis that developmental exposure to PBDEs produce neurobehavioral and hypothalamic OXT deficits in a TH-dependent manner. Materials and Methods: C57BL/6N dams were exposed human relevant doses of the penta-PBDE mixture, DE-71, at 0.1 mg/kg/d (L-DE-71), 0.4 mg/kg/d (H-DE-71) or with corn oil vehicle control (VEH/CON) for 10 wks (pre-conception: 4 wk, gestation: 3 wk, lactation: 3 wk). A subset of dams was treated with levothyroxine, a synthetic analogue of thyroxine (T4) (8 μg/100 g bw; GD 12-PND 21). Other dams were administered the thyroid synthesis inhibitor, 6-propyl-2-thiouracil (PTU; 50 mg/L; GD 14-PND 21). Results: Compared to VEH/CON, T4 and insulin-like growth factor-1 were attenuated in L-DE-71 dams at PND 0 but normalized in L-DE-71 + T4. In contrast, dam plasma OXT was not altered by DE-71 and elevated by T4 supplementation. L-DE-71 adult male and female offspring showed deficient social novelty preference; maternal T4 supplementation prevented this only in females. In contrast, T4 supplementation was equally effective at normalizing exaggerated repetitive behavior in L-DE-71 male and female offspring. DE-71 reduced OXT immunofluorescence IOD in the paraventricular nucleus of the hypothalamus (PVH) in male (L- and H-DE-71) and female offspring (L-DE-71) and in supraoptic nucleus (SON) in male offspring (L-DE-71) at PND 30. T4 supplementation normalized OXT content in L-DE-71 female and H-DE-71 male PVH. DE-71 had no effect on plasma OXT but was upregulated in VEH/CON +T4 female and DE-71+T4 male offspring. RT-qPCR analysis performed at PND15-30 showed that L-DE-71 downregulated hypothalamic Trh and cortical Oatp1c1 and Dio3 in females and upregulated hypothalamic Dio2, Esr1 and Esr2 and cortical Oatp1c1 in males. PTU’s actions do not exactly mimic those of DE-71. Conclusions: These results suggest that PBDEs disrupt social behavior and central OXT in a TH-dependent and sex-dependent manner. We provide novel information about possible TH-responsive genes that may contribute to neurodevelopmental disorders such as ASD. This work is supported by a Society of Toxicology Syngenta Fellowship Award in Human Health Applications of New Technologies and University of California President's Pre-Professoriate Fellowship to E.V.K. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.