Multigenerational exposure to DEHP drives dysregulation of imprinted gene Snurf to impair decidualization

Abstract

Phthalate-induced female reproductive health issues, particularly those related to di (2-ethylhexyl) phthalate (DEHP), are growing global concerns. Although most studies have focused on single-generation exposure, studies on prolonged DEHP exposure across multiple generations are limited. This study assessed the effects of multigenerational DEHP exposure on endometrial decidualization, which is crucial for embryo implantation. The results showed that sustained DEHP exposure over three generations exacerbated decidualization injury and led to adverse pregnancy outcomes. RNA sequencing revealed upregulation of the imprinted gene Snurf in the decidua, with changes that may not depend on alterations in DNA methylation. Knockdown of Snurf significantly alleviated in vitro decidualization deficiency induced by mono(2-ethylhexyl) phthalate (MEHP), the biologically active metabolite of DEHP. Proteomic analysis and the AlphaFold 3 algorithm indicated that Stn1 is a downstream target of Snurf, with silencing Stn1 resensitizing Snurf-knockdown stromal cells to MEHP. Human decidual stromal cells (hDSCs) from healthy participants showed sensitivity to MEHP, with the inhibition of decidualization. Epidemiological data from the 2017–2018 National Health and Nutrition Examination Survey (NHANES) indicated a positive association between DEHP exposure and female infertility. This study highlighted the cumulative toxic effects of multigenerational DEHP exposure on female reproduction and revealed the contribution of imprinted genes.