Morales, 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↗

bioRxiv2023

Selective effects of estradiol on human corneal endothelial cells

Fuchs endothelial corneal dystrophy (FECD) results from genetic and environmental factors triggering mitochondrial and oxidative stress in corneal endothelial cells (CEnCs) leading to CEnC death and corneal opacification. FECD is more common in women than men, but the basis for this observation is unknown. Because FECD is commonly diagnosed around the time of the menopausal transition in women when estrogen levels decrease precipitously, we studied the effects of the potent estrogen,17-{beta} estradiol (E2) on growth, oxidative stress, and metabolism in primary cultures of human CEnCs (HCEnCs) under conditions of physiologic 2.5% O2 ([O2]2.5) and under hyperoxic stress ([O2]A: room air + 5% CO2). We hypothesized that E2 would counter the stresses of the hyperoxic environment in HCEnCs. HCEnCs were treated {+/-} 10 nM E2 for 7-10 days at [O2]2.5 and [O2]A followed by measurements of cell density, viability, reactive oxygen species (ROS), mitochondrial morphology, oxidative DNA damage, ATP levels, mitochondrial respiration (O2 consumption rate [OCR]), and glycolysis (extracellular acidification rate [ECAR]). There were no significant changes in HCEnC density, viability, ROS levels, oxidative DNA damage, OCR, and ECAR in response to E2 under either O2 condition. We found that E2 disrupted mitochondrial morphology in HCEnCs from female donors but not male donors at the [O2]A condition. ATP levels were significantly higher at [O2]2.5 compared to [O2]A in HCEnCs from female donors only, but were not affected by E2. Our findings demonstrate the overall resilience of primary HCEnCs against hyperoxic stress. The selective detrimental effects of hyperoxia and estradiol on HCEnCs from female but not male donors suggests mechanisms of toxicity based upon cell-sex in addition to hormonal environment.

cell biology↗