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September 10, 2025Open Access

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

Key Points

Adult male mice exposed to PBDEs through maternal transfer exhibited enduring autism-like behaviors and neurochemical changes.
Findings revealed significant alterations in neurobehavioral phenotypes, particularly short- and long-term memory, with no change in anxiety-like behaviors.
Polybrominated diphenyl ethers were administered to pregnant mice and their offspring, allowing for the evaluation of behavioral and molecular outcomes.
The study emphasizes the critical role of early exposure to neuroendocrine disruptors like PBDEs in shaping social and cognitive functioning.

Abstract

Background: 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 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. Methods: 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 bw/d for 10 weeks, spanning three weeks prior to gestation through the end of lactation at postnatal day (PND) 21. Results: Mass 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. Conclusions: These 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.

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