Polybrominated Diphenyl Ethers in Human Follicular Fluid Dysregulate Mural and Cumulus Granulosa Cell Gene Expression

Abstract

Polybrominated diphenyl ethers (PBDEs), a major class of flame retardants incorporated into numerous consumer products, leach out into dust resulting in widespread exposure. There is evidence from in vitro and in vivo animal studies that PBDEs affect ovarian granulosa cell function and follicular development, yet human studies of their association with female infertility are inconclusive. Here, we tested the hypothesis that exposure to the PBDEs in follicular fluid is associated with dysregulation of gene expression in the mural and cumulus granulosa cells collected from women undergoing in vitro fertilization by intracytoplasmic sperm injection. The median concentration of the ∑ 10PBDEs detected in the follicular fluid samples (n = 37) was 15.04 pg/g wet weight. RNA microarray analyses revealed that many genes were differentially expressed in mural and cumulus granulosa cells. Highest vs lowest quartile exposure to the Σ 10PBDEs or to 2 predominant PBDE congeners, BDE-47 or BDE-153, was associated with significant effects on gene expression in both cell types. Mural granulosa cells were generally more sensitive to PBDE exposure compared to cumulus cells. Overall, gene expression changes associated with BDE-47 exposure were similar to those for ∑ 10PBDEs but distinct from those associated with BDE-153 exposure. Interestingly, exposure to BDE-47 and ∑ 10PBDEs activated the expression of genes in pathways that are important in innate immunity and inflammation. To the best of our knowledge, this is the first demonstration that exposure to these environmental chemicals is associated with the dysregulation of pathways that play an essential role in ovulation.

The effects of endocrine‐disrupting chemicals on ovarian‐ and ovulation‐related fertility outcomes

“…Specifically, levels of PBDEs in the mural cells were associated with more activated genes in pathways important for innate immunity and inflammation (Lefèvre et al, 2021). Since mural granulosa cells are responsible for producing inflammatory markers during ovulation, these findings suggest that PBDE exposure may disrupt this crucial pathway in the human ovary.…”

“…This same group identified that mural granulosa cells are more susceptible than cumulus cells to toxicities caused by PBDEs in follicular fluid from samples collected from women undergoing IVF. Specifically, levels of PBDEs in the mural cells were associated with more activated genes in pathways important for innate immunity and inflammation (Lefèvre et al, 2021 ). Since mural granulosa cells are responsible for producing inflammatory markers during ovulation, these findings suggest that PBDE exposure may disrupt this crucial pathway in the human ovary.…”

An Oxidative Stress-Related Gene Signature in Granulosa Cells Is Associated with Ovarian Aging

“…These inconsistences can be attributed to the fact that the GCs used are slightly different in nature. First, there are important functional differences as well as distinct gene expression profiles between cumulus cells that are in direct contact with the oocyte and mural granulosa cells, which surround the follicle antrum [ 47 , 48 ]. Second, GCs from follicles of different stages show differential gene expression profiles [ 47 , 49 ].…”

Effects of sponge-derived polybrominated diphenyl ethers on human cancer cell α-N-acetylgalactosaminidase and bacterial α-d-galactosidase and their antioxidant activity

“…[2][3][4][5] PBDEs, together with their hydroxylated and methoxylated analogues, have been identied ubiquitously in humans, wildlife, and marine biota. [6][7][8] Toxicology reports indicate that PBDEs cause thyroid dysfunction, 9,10 affect ovarian granulosa cell function and follicular development, 11 and interfere with the male reproductive system. 12 Moreover, they have neurotoxic, 13 carcinogenic 14 and other toxic effects on reproductive health, 15 including the effects on reproductive outcomes among women undergoing assisted reproductive technologies 16 and declining semen quality.…”