Ozone exposure during implantation impairs offspring metabolic processes in a sex-specific manner in rats
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Intrauterine growth restriction, attributable to adverse prenatal environments, is implicated in the increasing prevalence of cardiometabolic disease. We have shown that peri-implantation ozone exposure impairs fetal weight. Accordingly, this study aimed to determine if ozone-induced fetal growth restriction increases susceptibility to postnatal metabolic disease. Pregnant Long-Evans rats were exposed to 0.8 ppm ozone or filtered air during gestation days 5 and 6 (4 hr/d). Then, at postnatal day 45 subsets of male and female offspring were challenged with a 3-day high fat diet (HFD). In offspring from ozone-exposed dams, HFD challenge exacerbated caloric intake and reduced energy expenditure. However, regardless of diet, females from ozone-exposed dams had reduced hepatic expression of lipolytic genes (Cpt1, Cpt2, Pparα) and bile acid regulatory genes (Fxr, Fgfr4, Hnf4α, Bsep). Furthermore, postnatal HFD challenge of female offspring from ozone-exposed dams altered hepatic gene expression related to insulin signaling (Insr, Irs1, Irs2), inflammation (Tnfα), gluconeogenesis (Fbp1, G6pc), cholesterol synthesis (Mvd), and bile acid signaling (Cyp27a1, Cyp8b1, Cyp7b1, 3βHSD3, βKlotho). Notably, female offspring from ozone-exposed dams had reduced hepatic triglycerides and circulating insulin levels relative to controls. In male offspring from ozone-exposed dams, alterations in gene expression were mainly attributable to HFD challenge – affecting lipolysis (Cpt1, Cpt2, Pparα) and cholesterol synthesis (Hmgcs1, Mvd1), but not bile acid signaling. These male offspring also reduced hepatic triglycerides, increased circulating cholesterol, and increased body adiposity. Together, these findings demonstrate a sex-specific predisposition to metabolic alterations in terms of the hepatic responses to pre- and post-natal stressors, highlighting the importance of considering sex in risk assessment of hepatoxicity and metabolism. This study provides insight on the effects of acute gestational ozone exposure on systemic metabolic status in offspring, which may increase their susceptibility to develop metabolic diseases when challenged with environmental stressors. Does not reflect US EPA policy.