Kern, M. J. | bioRxiv Science

bioRxiv2025

Effects of combined prenatal exposure to air pollution and maternal stress on immune and dopaminergic gene expression in the gut-brain axis

Air pollution and maternal stress during pregnancy are both risk factors for neurodevelopmental disorders and often converge on the same communities. Epidemiological and animal studies suggest that maternal psychosocial stress may worsen the effects of air pollutants on neurodevelopmental outcomes. Previous work utilizing a mouse model of combined prenatal exposure to diesel exhaust particles (DEP) and maternal stress (MS) has found numerous sex-specific effects of DEP/MS exposure on neuroimmune outcomes, dopamine receptors, the gut-brain axis, and social behavior. However, it is unclear how broadly the immune landscape is shifted in the brain and intestinal epithelium following DEP/MS. Here, we analyzed immune gene expression in 5 brain regions important for social behavior and in 3 regions of the intestinal epithelium in both male and female offspring following either DEP/MS or control exposure. We found several interesting overall patterns. First, changes in expression of immune genes such as CD11b and Tlr4 were concentrated in the nucleus accumbens and hippocampus. Tlr4 and Il-17ra mRNA also increased in the jejunum and colon following DEP/MS, but only in females. Second, in the nucleus accumbens, catecholamine-O-methyltransferase (Comt) and dopamine transporter 1 (Slc6a3) gene expression were increased following DEP/MS indicating increased dopamine degradation at and reuptake from the synapse, respectively. Additionally, Drd2 mRNA was decreased following DEP/MS in males. Finally, we observed numerous sex differences in immune gene expression regardless of treatment in both the brain and gut. Together, these findings suggest the nucleus accumbens is a key site for neuroimmune and dopaminergic changes following DEP/MS exposure and indicate persistent female-specific changes in intestinal immunity following these prenatal exposures. HighlightsO_LICd11b and Tlr4 mRNA is altered in the NAc and Hipp following DEP/MS C_LIO_LISeveral genes indicate reduced dopamine signaling in the NAc following DEP/MS in both sexes C_LIO_LIIntestinal Tlr4 and IL-17ra mRNA is increased in females only following DEP/MS C_LI

neuroscience↗

bioRxiv2025

Effects of combined prenatal exposure to air pollution and maternal stress on social behavior and oxytocin and vasopressin systems in male and female mice

Prenatal exposures to air pollution and maternal psychosocial stress are each associated with increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD) and epidemiological work suggests that concurrent exposure to these risk factors may be particularly harmful. This is important given that the same populations often bear the brunt of both toxicant and psychosocial stress burdens. Social impairments are a defining symptom in ASD. Previous work modeling combined prenatal exposure to diesel exhaust particles (DEP) and maternal stress (MS) in rodents has found male-biased social deficits in offspring, as well as changes to neuroimmune processes and the gut microbiome. However, the precise neural circuits on which these exposures converge to impact social behavior is unclear. Oxytocin (OXT) and vasopressin (AVP) are neuropeptides critical to the regulation of social behavior across species, signaling primarily at the oxytocin receptor (Oxtr) and vasopressin V1a receptor (V1aR) in the brain. Here, we hypothesized that OXT and/or AVP expression would be reduced in the brain following DEP/MS exposure. Following prenatal exposure to DEP/MS or the vehicle/control condition (VEH/CON), we measured maternal and offspring outcomes during the perinatal period, social and anxiety-like behavior during adolescence, OXT and AVP cell/fiber density and Oxtr and Avpr1a mRNA expression in early adulthood in several brain regions in both males and females. We observed a decrease in interaction time in DEP/MS males as compared to VEH/CON in the sociability assay and a decrease in social novelty preference in DEP/MS females as compared to VEH/CON. No effects of sex or treatment were observed on OXT or AVP cell number or fiber density in the hypothalamic regions assessed. However, numerous sex differences were observed in Oxtr and Avpr1a mRNA. Moreover, Avpr1a mRNA was significantly increased following DEP/MS exposure in the nucleus accumbens in both sexes and tended to increase in the dorsal hippocampus. Conversely, Avpr1a mRNA tended to decrease in the amygdala in both sexes following DEP/MS exposure. Together, these findings suggest that DEP/MS exposure has a stronger impact on female social behavior than previously observed. Moreover, while DEP/MS exposure does not appear to impact OXT or AVP expression in the brain, V1aR expression is modulated by DEP/MS exposure in several brain regions. HighlightsO_LIPrenatal DEP/MS reduces social novelty preference in females C_LIO_LIPrenatal DEP/MS does not alter OXT or AVP cell number in the PVN C_LIO_LIPrenatal DEP/MS does not alter OXT or AVP fiber density in the LH, AH, or MPOA C_LIO_LIPrenatal DEP/MS increases Avpr1a mRNA in the NAc C_LIO_LIPrenatal DEP/MS tends to decrease Avrp1a mRNA in the AMY and increase in dHipp C_LI

neuroscience↗