Maternal Exposure to Ozone During Implantation Promotes a Feminized Transcriptomic Profile in the Male Adolescent Liver

Maternal exposure to ozone during implantation results in reduced fetal weight gain in rats. Offspring from ozone-exposed dams demonstrate sexually dimorphic risks to high-fat diet feeding in adolescence. To better understand the adolescent hepatic metabolic landscape following fetal growth restriction, RNA sequencing was performed to characterize the effects of ozone-induced fetal growth restriction on male and female offspring. Pregnant Long-Evans rats were exposed to filtered air or 0.8 ppm ozone for 4 hours on both gestation days 5 and 6 (n = 6/group). At approximately postnatal day 48, liver tissue was obtained for RNA sequencing from offspring. Peri-implantation exposure to ozone in the dam had greater effects on hepatic gene expression in male offspring than in the females. Interestingly, heatmaps of these differentially expressed genes suggested that male offspring from ozone-exposed dams had a transcriptomic pattern like that of female offspring. Using a filtered set of highly female-predominant genes (n = 390), 57% were upregulated in the male offspring from ozone-exposed dams. Upregulated canonical pathways included sirtuin and orexin signaling, estrogen receptor signaling, and integration of energy metabolism. Relatively few genes altered in the male offspring from ozone-exposed dams were associated with endpoints of sexual maturity, signifying the likely source of the observed feminization was not attributed to sex hormones. This study provides initial evidence that growth restriction in utero may increase the risk of hepatic feminization in male offspring. Additional work is needed to further understand the relationship between developmental undernutrition and feminization in the male liver.