Toxicant-Induced Social Deficits Co-Occur with Altered Olfactory Discrimination, Social Cue Signaling, and Deregulated Prosocial Neuropeptides

The prevalence of autism spectrum disorders (ASD) behaviors, marked by deficient social reciprocity and communication, has increased exponentially—now affecting 1 in 36 US children. Polybrominated diphenyl ethers (PBDEs) are flame retardants commonly detected in human tissues worldwide that have been associated with disrupted thyroid hormones (TH), hyperactivity, and lowered IQ in infants or toddlers. Our lab has previously shown that maternal transfer of PBDEs to female mice offspring produces deficits in social recognition memory, olfactory discrimination of social odors, and deregulated brain social neuropeptide genes. Our pilot data also show similar social behavioral deficits in exposed male offspring; however, the neuromolecular mechanisms are unknown. We tested the hypothesis that, in male mice, exposure to DE-71, a penta-PBDE mixture, alters olfactory discrimination, social stimuli signaling, and expression of prosocial neuropeptide gene markers for oxytocin (Oxt), vasopressin (Avp) and PACAP (Adcyap1) and/or their receptors Avp1ar, Oxtr, Adcyap1r1 in regions of the social brain network (SBN). Mouse dams were subjected to either 1) 0.1 mg/kg/d DE-71 (L-DE-71), 2) 0.4 mg/kg/d DE-71 (H-DE-71), or corn oil vehicle (VEH/CON) for 10 weeks with or without TH supplementation (T4, 5.7-9.9 ug/100g bw) administered from gestation day 12 to postnatal day 21. Adult male offspring were examined for their ability to discriminate social and non-social odors using the olfactory habituation/dishabituation test (OHT). Relative to VEH/CON, L-DE-71 males showed increased dishabituation for social odor 2. Using c-FOS immunohistochemistry, brain sections from VEH/CON male offspring exposed to 3 min of social stimulation showed increased c-Fos cell counts (normalized to ROI area) in the prelimbic (PrL) cortex, an area participating in social behavior. This number was reduced in socially activated L-DE-71 males and females but not L-DE-71+T4 females. Brain sections were micropunched to isolate RNA from specific anatomical regions. RT-qPCR was used to analyze expression of prosocial gene markers relative to ActB and group comparisons were made vs VEH/CON. Adcyap1r1 was upregulated in H-DE-71 of the supraoptic nucleus (SON) (p<.05, n=9-15) and paraventricular nucleus (PVN) (p<.05, n=9-12). Oxt was upregulated in L-DE-71 PVN (p<.05, n=9-13) and Oxtr was downregulated in L-DE-71 amygdala (AMG) (p<.05, n=12-16). Avp was upregulated in L-DE-71 in PVN (p<.05, n=10-13) and downregulated in both H-DE-71 AMG (p<.05, n=9-12) and L-DE-71 lateral septum (LS) (p<.05, n=9-10). These results suggest that developmental exposure to PBDEs reprogram circuits regulating olfactory discrimination and social cue signaling in a T4-dependent manner. Deregulated social neuropeptidergic systems resulting from environmentally-triggered neurodevelopmental reprogramming may contribute and serve as novel therapeutic targets for the mitigation of ASD. This work was supported by UCR Undergraduate Research Minigrant awards to NL and LC and RISE Fellowships to NL and NJ. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.