Enduring autism‐like phenotypes and deregulated hypothalamic prosocial peptides after early‐life exposure to indoor flame retardants in male C57BL /6 mice

Abstract

Polybrominated 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 comorbid with cognitive deficits and sensory abnormalities. 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 neuroendocrine deficits in male offspring. C57Bl6/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 b.w./day for 10 weeks, spanning from 3 weeks prior to gestation through the end of lactation at postnatal day (PND) 21. Mass spectrometric analysis indicated a dose‐dependent transfer of PBDEs (in ppb) to brains of F1 male offspring at PND 30, with reduction in levels by PND 110. DE‐71‐exposed adult F1 male offspring displayed ASD‐relevant abnormal neurobehavioral phenotypes, including impaired social novelty preference (SNP) despite intact general sociability and exaggerated repetitive behavior. There were also milder effects on long‐term social recognition memory (SRM). DE‐71‐exposed mice also displayed altered olfactory discrimination of social odors without altered odor preference for non‐social odors, impaired novel object recognition memory, and reduced open field habituation relative to VEH/CON. However, no changes were observed in sensorimotor, anxiety‐, or depressive‐like behaviors. At the molecular level, DE‐71‐exposed males displayed deregulated gene markers of prosocial neuropeptides, oxytocin, vasopressin, and PACAP systems in hypothalamic and forebrain regions. 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. Peripheral OXT was increased in L‐DE‐71 males, while no changes in plasma AVP were observed. These findings demonstrate that developmental PBDE exposure produces enduring behavioral and neuroendocrine phenotypes that resemble core domains of ASD, which may result from early neurodevelopmental reprogramming within central social and memory networks.