Exogenous, Evoked Oxytocin System Modulation or Thyroid Hormone Supplementation Reverses ASD-Like Deficits Produced by Developmental Pollutant Exposure

Environmental toxicant exposure may be a contributing factor to the rising prevalence of Autism Spectrum Disorder (ASD). We have reported altered behavior symptoms in two ASD core domains and social neuropeptide expression in offspring from C57BL/6 mouse mothers exposed to human-relevant concentrations of polybrominated diphenyl ethers (PBDEs). Recently, we found that DE-71 markedly reduces the total number of OXTergic cells in the paraventricular nucleus (PVH) and/or the supraoptic nucleus of the hypothalamus in parallel with prevention of short-term social recognition memory, in a TH-dependent manner. We hypothesized that the OXT-depleting effects of thyroid-disruptive PBDEs drive the ASD-like phenotype observed since THs regulate oxytocin (OXT), vasopressin (AVP) and their receptors, that are critical for social recognition memory (SRM). On a social novelty preference (SNP) test, modification of endogenous OXTergic signaling with brain-penetrant melanocortin 4 receptor (MC4R) agonist, Ro21-3225 (7.5, 15 mg/kg ip), or applying exogenous OXT intranasally (iOXT, 9.2 IU/kg) rescued normal behavior in FMR1-/- females and males but not C57BL/6 females exposed to 0.1 mg/kg DE-71, a penta-PBDE mixture (L-DE-71), suggesting deficient OXTR in L-DE-71 females. In contrast, iAVP (9.2 IU/kg) rescued deficient SNP in both L-DE-71 males and females. Since OXT and AVP are highly homologous peptides that engage in receptor crosstalk, we used pharmacological blockade of OXT receptor (OXTR) with antagonist L371,257 prior to peptide administration to isolate the specific contribution of OXTR to the rescue of short-term SRM. SRM improvement after iOXT but not iAVP, which likely works via V1a receptors, was abolished by OXTR block in L-DE-71 males. In contrast, SRM improvement after iAVP in females was eliminated after OXTR block. Together, these results suggest that OXTRs in L-DE-71 females may have reduced affinity for OXT, preventing SRM rescue by iOXT but not iAVP. We tested the hypothesis that chronic OXT administration during early development would restore OXT and rescue social deficits in OXTR-deficient L-DE-71 females. Chronic intranasal oxytocin (iOXT; 11.4-21.7 IU/kg/d) during postnatal days (P) 7-21 improved long-term SRM in L-DE-71 juvenile females and males and ameliorated ASD-relevant exaggerated repetitive behavior on a marble burying test only in L-DE-71 juvenile males. Lastly, we used chemogenetic activation of PVH OXTergic neurons and their synaptic projections to OXTR-containing limbic targets, to test for reversal of DE-71-produced SRM deficiency. In comparison to saline controls, administration of DREADD ligand CNO (3 mg/kg bw) to adult mice transfected with AAV driving hM3Dq-mCherry under the OXT promoter rescued short-term SRM in L-DE-71 males and females. Therefore, the abnormal SRM phenotype was reversed likely due to OXT saturation at deficient OXTRs of forebrain-projecting PVH OXT-ergic axons that drive short-term SRM. Modification of the central OXT system via TH supplementation, endogenous or evoked OXT and chemogenetic activation of PVH OXTergic neurons can rescue social recognition memory in offspring exposed perinatally to PBDEs in a sex-dependent manner. Specifically, they reveal that endocrine disruption by PBDEs can produce female-biased OXTR alterations that constrain pharmacological rescue after closing of critical periods. Collectively, our data elucidates the therapeutic potential of direct and indirect targeting of the oxytocin system to improve ASD-like symptoms in an environmental ASD model. This abstract was presented at the American Physiology Summit 2026 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.