Luvsanravdan, N. | Search bioRxiv

bioRxiv2025

Enduring Autism-like Phenotypes and Deregulated Hypothalamic Prosocial Peptides After Early-Life Exposure to Indoor Flame Retardants in Male C57BL/6 Mice

BackgroundPolybrominated diphenyl ethers (PBDEs) are neuroendocrine disrupting chemicals that produce adverse neurodevelopmental effects. PBDEs have been implicated as risk factors for autism spectrum disorder (ASD), which is characterized by abnormal psychosocial functioning and is commonly accompanied by co-morbidities such as cognitive and attentional deficits. Here, we used a mouse model with translationally relevant exposure to establish direct causal evidence that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in male offspring. MethodsC57Bl6/N mouse dams were exposed to a commercial PBDE mixture, DE-71, via oral administration of 0 (vehicle control, VEH/CON), 0.1 (L-DE-71), or 0.4 (H-DE-71) mg/kg bw/d for 10 weeks, spanning three weeks prior to gestation through the end of lactation at postnatal day (PND) 21. ResultsMass spectrometric analysis indicated dose-dependent transfer of PBDEs (in ppb) to brains of F1 male offspring at PND 30, with reduction in levels by PND 110. Adult F1 male offspring displayed ASD-relevant neurobehavioral phenotypes, including impaired short- and long-term social recognition memory (SRM), despite intact general sociability, and exaggerated repetitive behavior. Exposed mice also displayed altered olfactory discrimination of social odors, impaired novel object recognition memory, and reduced open field habituation. However, no changes were observed in anxiety-like, sensorimotor, or depressive-like behaviors relative to VEH/CON. At the molecular level, DE-71 exposed males displayed deregulated gene markers of prosocial neuropeptides. Oxt was upregulated in the paraventricular nucleus (PVN); Avp was upregulated in the PVN and bed nucleus of the stria terminalis (BNST) but downregulated in the lateral septum (LS); Avp1ar and Adcyap1 were upregulated in the BNST; and Adcyap1r1 was upregulated in the PVN, supraoptic nucleus (SON), and BNST. ConclusionsThese findings demonstrate that developmental PBDE exposure produces enduring behavioral and neurochemical phenotypes that resemble core domains of ASD, which may result from early neurodevelopmental reprogramming within central social and memory networks.

neuroscience↗

bioRxiv2025

Maternal Thyroid Supplementation Prevents Autistic-relevant Social Behavior and Hypothalamic Oxytocin Depletion Produced by Developmental Exposure to Environmental Toxicants

Environmental toxicants that target the developing brain are suspected of contributing to autism spectrum disorder risk but causative evidence is lacking. We and others have shown that the indoor flame retardants, polybrominated diphenyl ethers (PBDEs), reduce prosocial behavior, however, few studies have assessed the central targets and underlying mechanisms. PBDEs are well established endocrine disruptors of the expanded thyroid system, which also regulates the prosocial neuropeptides oxytocin (OXT) and vasopressin (AVP) and their hypothalamic signaling. The potential role of PBDE-induced thyroid hormone (TH) deregulation in mediating disruption of central OXT and ASD-like social behavior deficits remains unmapped. To address this gap, we conducted a study in C57BL6/N mice that examined behavioral and neuromolecular reprogramming after developmental exposure to the commercial PBDE mixture, DE-71, and evaluated the therapeutic potential of TH supplementation. Dams were exposed daily during gestation and lactation to corn oil vehicle, low dose (0.1 mg/kg) and high dose (0.4 mg/kg) of DE-71 with or without concurrent L-thyroxine (+mT4). In offspring, dose-dependent ASD-relevant behavioral responses and central neuroendocrine OXT neuron depletion after developmental PBDE exposure was prevented with mT4. mRNA transcripts for the TH transporter Mct8, deiodinase (Dio3) and estrogen receptor beta (Esr2) expressed on OXT neurons in PVH were upregulated in low dose females. In contrast, Mct8 and Dio3 were downregulated in low dose males. These findings uncover sex-specific mechanisms of PBDE-induced reprogramming of TH-regulated pathways in hypothalamic neuroendocrine cells leading to depleted central OXT signaling and ultimately ASD-relevant phenotypes. Importantly, we provide novel evidence of the therapeutic potential of maternal thyroid supplementation against toxicant-induced neurodevelopmental disorders.

neuroscience↗