Gestational Glucocorticoids' Exposure Impairs Vascular Contractility in Male Offspring Mice With Transgenerational Effects.

Abstract

BACKGROUND: The application or excessive exposure to glucocorticoids constitutes a common adverse factor endured by intrauterine fetuses. Gestational glucocorticoids' exposure is intimately associated with the risk of postnatal vascular problems; however, whether the vascular problem can be transgenerationally inherited remains indistinct. In this study, a mouse model of gestational glucocorticoids' exposure was established, aiming to discover the abnormal phenotype of acquired vascular function of the offspring and clarify the epigenetic mechanism of the transgenerational transmission of the relevant abnormal phenotypes. METHODS: To model gestational glucocorticoid exposure, pregnant mice received intraperitoneal injections of dexamethasone (a synthetic glucocorticoid) on gestational days 12, 14, 16, and 18. Male offspring (F1) derived from dexamethasone group-exposed pregnancies were bred with wild-type females to generate F2 progeny, and this breeding strategy was repeated to produce F3 offspring. Adult male offspring from all 3 generations were subsequently analyzed. RESULTS: We observed that gestational dexamethasone group exposure induced a modest but consistent elevation in systolic blood pressure across F1 to F3 male offspring, accompanied by enhanced Ang II (angiotensin II)-mediated vascular contractility. Mechanistically, dexamethasone group exposure significantly reduced DNA methylation in the Agtr1a (Ang II receptor subtype A) gene promoter within F1 offspring vasculature, leading to upregulated Agtr1a expression and heightened oxidative stress via the AT1R (Ang II receptor 1)/NOX (nicotinamide adenine dinucleotide phosphate oxidase) 2/reactive oxygen species axis. This cascade potentiated Ang II-induced vascular contractility. Moreover, these acquired abnormal vascular problems can be stably inherited and transgenerationally transmitted through the alteration of the DNA methylation pattern of the Agtr1a gene in sperm. CONCLUSIONS: This study demonstrates that gestational glucocorticoids' exposure triggers transgenerational inheritance of vascular dysfunction in male offspring via DNA methylation reprogramming, providing direct evidence for the epigenetic transmission of acquired traits. These findings advance our understanding of intergenerational disease mechanisms and offer novel insights for clinical strategies aimed at mitigating the adverse effects of gestational glucocorticoid therapy.