Maternal ozone exposure alters hepatic susceptibility to postnatal stressors differentially by sex.
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We have reproducibly demonstrated that exposure to ozone during implantation receptivity alters fetal growth trajectories, with more severe effects in the male sex. Aligned with the Developmental Origins of Health and Disease hypothesis, fetal growth restriction has been associated with a heightened risk of metabolic disease in epidemiological cohorts, which has been well demonstrated in controlled in vivo investigations. Considering our model of ozone-induced fetal growth restriction, we have performed a series of studies investigating the metabolic susceptibility in offspring of dams exposed to ozone during early pregnancy. In our work with a high-fat diet, we have found that maternal ozone exposure preferentially increases the risk of obesity in the male offspring. Interestingly, female littermates from ozone-exposed dams demonstrated protection from high-fat diet-induced increases in adiposity. Molecular data from this study suggested a critical role of the liver in driving the sex-specific phenotypes observed following maternal ozone exposure. To further assess the role of prenatal ozone exposure and sex differences in hepatic susceptibility to metabolic stressors, we next exposed offspring to ozone for 1 day per week over 3 weeks following weaning. Male offspring from ozone-exposed dams that were postnatally challenged with ozone displayed an increase in the number of differentially expressed genes compared to their female littermates (upregulated: 1,219 vs. 413; downregulated: 1,106 s. 522). These data indicated an increase in hepatic lipid metabolism in the male sex, which was further supported by reductions in hepatic triglycerides and cholesterol and an increase in serum cholesterol. Such metabolic effects were not present in female offspring, closely mirroring our findings with a high-fat diet. Collectively, we report differential programming of metabolic flexibility between male and female offspring in our ozone-induced model of fetal growth restriction. Our work also suggests the likelihood of sexual dimorphism in placental energy metabolism as a critical step in hepatic reprogramming, suggesting that the origin of such differences may occur well before birth. This abstract does not reflect US EPA policy.