Impact of DEHP on mitochondria-associated endoplasmic reticulum membranes and reproductive toxicity in ovary

Ecotoxicol Environ Saf. 2024 Sep 1:282:116679. doi: 10.1016/j.ecoenv.2024.116679. Epub 2024 Jul 8.

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a widely recognized environmental endocrine disruptor that potentially impacts female reproductive function, although the specific mechanisms leading to such impairment remain unclear. A growing body of research has revealed that the endoplasmic reticulum and mitochondrial function significantly influence oocyte quality. The structure of mitochondria-associated endoplasmic reticulum membranes (MAMs) is crucial for facilitating the exchange of Ca2+, lipids, and metabolites. This study aimed to investigate the alterations in the composition and function of MAMs after DEHP exposure and to elucidate the underlying mechanisms of ovarian toxicity. The female mice were exposed to DEHP at doses of 5 and 500 mg/kg/day for one month. The results revealed that DEHP exposure led to reduced serum anti-Müllerian hormone levels and increased atretic follicles in mice. DEHP induced endoplasmic reticulum stress and disrupted calcium homeostasis in oocytes. Furthermore, DEHP impaired the mitochondrial function of oocytes and reduced their membrane potential, and promoting apoptosis. Similar results were observed in human granulosa cells after exposure to mono-(2-ethylhexyl) phthalate (MEHP, metabolites of DEHP) in vitro. Proteomic analysis and transmission electron microscopy revealed modifications in the functional proteins and structure of the MAMs, and the suppression of oxidative phosphorylation pathways. The findings of this investigation provide a new perspective on the mechanism underlying the reproductive toxicity of DEHP in females.

Keywords: Calcium homeostasis; DEHP; MAMs; Oocyte; Oxidative phosphorylation.

MeSH terms

  • Animals
  • Anti-Mullerian Hormone / metabolism
  • Apoptosis / drug effects
  • Calcium / metabolism
  • Diethylhexyl Phthalate* / toxicity
  • Endocrine Disruptors* / toxicity
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum* / drug effects
  • Endoplasmic Reticulum* / ultrastructure
  • Female
  • Granulosa Cells / drug effects
  • Humans
  • Mice
  • Mitochondria* / drug effects
  • Mitochondria* / ultrastructure
  • Oocytes / drug effects
  • Ovary* / drug effects
  • Reproduction / drug effects

Substances

  • Diethylhexyl Phthalate
  • Endocrine Disruptors
  • Calcium
  • Anti-Mullerian Hormone