Exposure to BDE-47 causes female infertility risk and induces oxidative stress and lipotoxicity-mediated ovarian hormone secretion disruption in mice

2,2,4,4-Tetrabromodiphenyl ether (BDE-47) has received considerable attention because of its high level in biological samples and potential developmental toxicity. Whether BDE-47 ingestion affects ovarian hormone secretion and the detailed underlying mechanism have not been clearly elucidated. The present study aimed to evaluate the toxicity of BDE-47 on ovarian hormone secretion and explored the underlying mechanism. The results showed that exposure to BDE-47 caused ovarian lipid deposition and ovarian hormone disruption accompanied by oxidative stress (OS) and downregulation of hormone biosynthesis-related proteins in mice. Mechanistically, using ovarian granulosa cells (GCs) as a cellular model, it was shown that BDE-47 inhibited two ovarian hormone secretion-associated pathways: i) BDE47 exposure induced OS via the Nrf2/HO-1 signaling pathway and further inhibited the expressions of ovarian hormone biosynthesis-related proteins, such as StAR, 3-beta HSD, CYP11A1, and CYP17A1; ii) BDE-47 induced endoplasmic reticulum (ER) stress, mitochondrial abnormalities, and lipotoxicity, which in turn disrupted the hormone biosynthesis process and inhibited ovarian hormone secretion. Interestingly, autophagy could promote hormone secretion via downregulating the transcription levels of PPAR gamma and C/EBP alpha involved in lipid deposition. Moreover, the reactive oxygen species (ROS) scavenger NAC and ER stress inhibitor 4-PBA not only inhibited the decrease in mitochondrial membrane potential but also blocked apoptosis induced by BDE-47, indicating that two individual pathways mediated apoptosis in GCs: the ER stress-mediated signaling pathway and the ROS-mediated mitochondrial signaling pathway. Together, these findings indicate the possible health risks of BDE-47 pollution areas to women, particularly affecting their ovarian hormone secretion.

Automated summary

This study found that exposure to BDE-47 can cause ovarian lipid deposition and hormone disruption accompanied by oxidative stress and downregulation of hormone biosynthesis-related proteins. Using a cellular model, it was shown that BDE-47 inhibits ovarian hormone secretion by interfering with specific pathways and inducing endoplasmic reticulum stress, mitochondrial abnormalities, and lipotoxicity. The findings suggest potential health risks of BDE-47 pollution areas to women, particularly affecting their ovarian hormone secretion.