Di (2-ethylhexyl) Phthalate decrease pregnancy rate via disrupting the microbe-gut-hypothalamic-pituitary-ovarian axis in mice.

Di (2-ethylhexyl) Phthalate (DEHP), a widely used plasticizer and endocrine disruptor, poses risks to human health, particularly reproductive function. Using a mouse model, we investigated how DEHP exposure impacts the hypothalamic-pituitary-ovarian (HPO) axis through gut microbiome disruption. DEHP decreased pregnancy rates by impairing ovarian function, activating hypothalamic astrocytes, and increasing neuregulin 1 (NRG1) expression. NRG1 binding to astrocyte ErbB2 receptors elevated prostaglandin E2 (PGE2) and gonadotropin-releasing hormone (GnRH), disrupting HPO axis homeostasis. Additionally, DEHP altered gut microbiota, destabilized microbial networks, and impacted β-glucuronidase-related taxa, leading to hormone fluctuations and reduced fertility. This study highlights gut microbiome perturbations as a novel mechanism linking DEHP exposure to reproductive dysfunction. Our study provides novel insights concerning perturbations of the gut microbiome and HPO axis and their functions as a potential new mechanism by which DEHP exposes interferes with the reproductive function-related human health.