Di-(2-ethylhexyl) phthalate induces endometriosis by modulating IGF-1 m6A methylation via the intestinal Odoribacter–butyric acid axis in female rats

Abstract

Endometriosis, a complex gynecological disorder characterized by aberrant growth of endometrial tissue outside the uterine cavity, poses a significant challenge to women's health. Emerging evidence implicates environmental pollutants, particularly di-(2-ethylhexyl) phthalate (DEHP), as potential contributors to endometriosis development. However, the precise molecular mechanisms underlying this effect remain poorly understood. Herein, we investigated the role of intestinal Odoribacter/butyric acid-mediated m6A methylation in METTL3/IGF-1 signaling in DEHP-induced epithelial-mesenchymal transition (EMT) and endometriosis in a rat model. Our study demonstrated that DEHP exposure alters the gut microbiota composition, leading to modulation of METTL3-mediated m6A modification in the insulin-like growth factor 1 (IGF-1) pathway. This modification enhances EMT in endometrial cells and promotes endometriotic lesion formation. We used a multi-layered approach, including 16S rRNA sequencing, targeted metabolomics, MeRIP-seq, quantitative polymerase chain reaction, western blotting, and immunohistochemistry, to elucidate the mechanistic role of intestinal Odoribacter/butyric acid pathway-mediated METTL3/IGF-1 m6A modification in DEHP-induced endometriosis. The results revealed a significant shift in microbial diversity and a corresponding increase in METTL3/IGF-1 m6A methylation in DEHP-exposed rats, which was directly linked to EMT markers such as E-cadherin and N-cadherin. Our findings reveal a novel gut microbiota-mediated mechanism by which DEHP exposure drives endometriosis via m6A methylation, providing valuable insights into the environmental and molecular basis of the disease. This study not only advances our understanding of the role of DEHP in endometriosis pathogenesis, but also suggests a putative intestinal Odoribacter–butyrate–METTL3/IGF-1 axis that may contribute to disease progression. However, these associations remain correlative, and causality requires further validation through functional experiments.