Is fetal growth restriction a risk factor for hepatic feminization? Findings from studies of ozone exposure during gestation.
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Exposure to ozone during implantation receptivity induces a model of fetal growth restriction in the rat. This exposure in early pregnancy appears to alter the susceptibility of the offspring to a high-fat diet, with male offspring from ozone-exposed dams experiencing greater levels of dyslipidemia and adiposity. To better understand the potential mechanisms underlying this response, we sought to characterize the effects of growth restriction on the hepatic transcriptome in adolescent rats. To produce fetal growth restriction, pregnant Long-Evans rats were exposed to 0.8 ppm ozone or filtered air for 4 hours on gestation days 5 and 6. No additional exposures occurred during gestation, and offspring were closely monitored for indices of growth after birth. Shortly after puberty (~postnatal day 45), male and female offspring were euthanized, and livers were collected for RNA sequencing (n=6/group). Maternal exposure to ozone-induced a small number of differentially expressed genes (DEGs) in females (49; q<0.05). In contrast, male offspring exhibited nearly 2,000 upregulated and 1,700 downregulated DEGs compared to male offspring from air-exposed dams. These gene changes were associated with signaling pathways such as EIF2, sirtuin, and estrogen receptor. Interestingly, heat maps suggested a pattern of gene expression changes in the ozone male offspring that were visually like that of female controls. Further analysis revealed that nearly 90% of DEGs in the male offspring from ozone-exposed dams were also upregulated in the female liver compared to the air control male liver. Of the most stringent female-biased genes (390; q<0.01, fold change ± 2.5), reflective of the genes most specific to the female liver compared to the male liver, 57% of them were also differentially expressed in the males from ozone-exposed dams. These genes were associated with increases in energy metabolism pathways, including sirtuin and orexin signaling, as well as positive associations with hepatic fibrosis and proliferation of liver cells. Our findings indicate that fetal growth restriction induced by maternal exposure to ozone during implantation results in hepatic feminization in male adolescent offspring. Collectively, results suggest that pollutant exposures that promote prenatal nutrient stress may program increased risks of liver disease in males through previously unrecognized mechanisms, namely hepatic feminization. This abstract does not reflect US EPA policy.