A tale of two livers: the impact of sex on hepatic gene expression in the adolescent rat exposed to ozone during implantation
On this page:
The postnatal health outcomes attributable to fetal undernutrition is suspected to be modulated by sex, with male offspring showing a higher risk for insulin resistance and hypertension compared to females. We have previously shown that exposure to 0.8 ppm ozone (4 hours/day) on gestation days 5 and 6 (implantation receptivity) impairs fetal growth in Long-Evans rats. Accordingly, the purpose of this study was to understand if prenatal ozone exposure and offspring sex altered hepatic metabolic signaling in adolescence. Livers from adolescent offspring (postnatal week 7) were assessed for global alterations in gene expression using RNA-seq (n=6/group). Differentially expressed genes (DEGs) were determined by Storey q-value<0.10 and further analyzed by Ingenuity Pathway Analysis (IPA). In air-exposed, control livers, a total of 6,518 DEGs between males and females were observed. Of the most significantly altered Canonical Pathways from Core Analysis, females displayed reductions in EIF2 Signaling and increases in pathways related to Senescence and Sirtuin Signaling compared to male controls. Exposure to peri-implantation ozone failed to induce gene or pathway-level alterations in females. Conversely, peri-implantation exposure to ozone in males resulted in 2,603 DEGs compared to air-exposed controls. Of these, 1,844 ozone-induced DEGs matched the directionality of altered genes observed in females. Consequently, the top IPAs observed in ozone-exposed males included EIF2 Signaling, Sirtuin Signaling, and the Regulation of eIF4 and p70S6K Signaling. As our data indicate, there are broad sex differences in adolescent gene expression, reflecting nearly 66% of all measurable hepatic genes in our study (6,518 / 9,470). Data also suggest that maternal peri-implantation ozone exposure might shift metabolic signaling in males to more closely resemble that of females during adolescence, with male offspring showing a 70% directional similarity with female-dominant DEGs. We hypothesize, therefore, that this basal alteration in metabolic gene expression (e.g., EIF2 and Sirtuin Signaling) likely relates to how the liver responds to prenatal environmental stressors. Lastly, we propose that investigating hepatotoxicity through a sexually dimorphic lens is critical in understanding the linkage between early life stressors and later life health impacts. This abstract does not reflect US EPA policy.