Early to midgestational testosterone excess leads to adverse lung programming in sheep offspring

Prenatal testosterone (T) excess programs sex-specific cardiovascular dysfunction in sheep offspring. Given the close reciprocal relationship with the cardiopulmonary system, we hypothesized that prenatal T excess would also adversely program the offspring's pulmonary system in a sex-specific manner from fetal life into adulthood. Pregnant ewes received intramuscular injections of T propionate (100 mg) or a vehicle control (C) twice weekly from gestational day (GD)30 to GD90 (term 147 days). Offspring lungs were collected at GD120 (n = 6 or 7 per group) and at 24 mo of age (n = 4-6 per group) for histological and molecular analyses. Data were analyzed with two-way ANOVA (fetal) and/or sex-specific stratified t tests for adults and Cohen's effect size analyses. Prenatal T significantly increased fetal lung collagen deposition in males. Prenatal T treatment had a significant overall treatment main effect on fetal lung apoptosis and the ratio of small to total blood vessels. Some adverse effects of prenatal T excess persisted into adulthood, including a significant increase in lung collagen in both sexes. Fetal lung transcriptome revealed differential enrichment of pathways involved in regulation of hormone biosynthetic process and neuron apoptotic process in T-treated males, whereas pathways related to bicarbonate transport and regulation of muscle cell differentiation were enriched in T-treated females. Overall, early to midgestational T excess adversely reprograms the offspring's lungs in a sex-specific manner, from fetal life extending into adulthood.NEW & NOTEWORTHY Early to midgestational testosterone (T) excess adversely programs lung development in a sex-specific manner, with effects extending from fetal life into adulthood. Fetal lung transcriptomics reveal distinct sex-specific molecular responses to prenatal T exposure. Together, these findings suggest that prenatal androgen excess may represent a developmental mechanism linking fetal lung programming to persistent pulmonary remodeling in adulthood.