Prenatal Steroids and Metabolic Dysfunction: Lessons from Sheep

Prenatal exposure to excess steroids or steroid mimics can disrupt the normal developmental trajectory of organ systems, culminating in adult disease. The metabolic system is particularly susceptible to the deleterious effects of prenatal steroid excess. Studies in sheep demonstrate that prenatal exposure to excess native steroids or endocrine-disrupting chemicals with steroidogenic activity, such as bisphenol A, results in postnatal development of numerous cardiometabolic perturbations, including insulin resistance, increased adiposity, altered adipocyte size and distribution, and hypertension. The similarities in the phenotypic outcomes programmed by these different prenatal insults suggest that common mechanisms may be involved, and these may include hormonal imbalances (e.g., hyperandrogenism and hyperinsulinemia), oxidative stress, inflammation, lipotoxicity, and epigenetic alterations. Animal models, including the sheep, provide mechanistic insight into the metabolic repercussions associated with prenatal steroid exposure and represent valuable research tools in understanding human health and disease. Focusing on the sheep model, this review summarizes the cardiometabolic perturbations programmed by prenatal exposure to different native steroids and steroid mimics and discusses the potential mechanisms underlying the development of adverse outcomes.