A Mixture Reflecting Polybrominated Diphenyl Ether (PBDE) Profiles Detected in Human Follicular Fluid Significantly Affects Steroidogenesis and Induces Oxidative Stress in a Female Human Granulosa Cell Line

Abstract

Brominated flame retardants are incorporated into consumer products to prevent flame propagation. These compounds leach into the domestic environment, resulting in chronic exposure. Pregnancy failure is associated with high levels of polybrominated diphenyl ethers (PBDEs), a major class of brominated flame retardants, in human follicular fluid, raising serious questions regarding their impact on female fertility. Our goal was to elucidate the effects of a mixture of PBDEs, similar to the profile found in human follicular fluid, on an immortalized human granulosa cell line, the KGN cell line. We showed that cell viability was altered and oxidative stress was induced as reflected by increased reactive oxygen species formation at 100 μM of the PBDE mixture. Transcriptomic analysis revealed that PBDE treatments of 1, 5, and 20 μM altered the expression of several genes involved in the reactive oxygen species signaling pathway. Significant dose-dependent reductions in progesterone and estradiol levels in the culture medium were measured after PBDE treatment; in parallel, the expression of genes involved in estradiol metabolism, namely CYP1A1, was up-regulated by 5 and 20 μM of the PBDE mixture. Treatment with 20 μM PBDE also increased the expression and secretion of the proinflammatory factor, IL-6, into the KGN cell culture medium. Our results demonstrate that PBDEs can alter human granulosa cell functions by inducing oxidative stress and disrupting steroidogenesis. These results indicate that PBDEs may be detrimental to ovarian functions and thus may adversely affect female reproductive health after chronic exposure.

Exploring reproductive associations of serum polybrominated diphenyl ether and hydroxylated brominated diphenyl ether concentrations among women undergoing in vitro fertilization

“…However, results from models only including first cycle outcomes were similar to our multiple-cycle models (Supplementary Tables SVI and SVII). Like many other studies, we measured PBDE and OH-BDEs in serum, while the measurement of chemicals in FF could potentially be an optimal medium for the specific microenvironments for reproductive studies (Lefevre et al, 2016;Huang et al, 2019). A previous IVF study comparing PBDEs in FF and serum detected weak but significant correlations (Kendall's tau-beta (T b ) =0.15-0.38) for congeners 47, 100 and 154 (Johnson et al, 2012).…”

Chronic BDE-47 Exposure Aggravates Malignant Phenotypes and Chemoresistance by Activating ERK Through ERα and GPR30 in Endometrial Carcinoma

“…The concentration used in this BDE-47 exposure model is based on the dose-response experiment and the data shown previously in other in vitro systems (34, 50–52). Recently, Kanaya compared with in vitro breast cancer cell culture treatment at dosage of 10 μM to the published human serum/tissue concentrations of PBDEs (BDE-47 included), and concluded that the maximum concentrations observed in human serum and tissue concentrations were ~1,300 and 350 times lower than 10 μM, respectively (32).…”

Serum measures of hexabromocyclododecane (HBCDD) and polybrominated diphenyl ethers (PBDEs) in reproductive-aged women in the United Kingdom

“…They have long half-lives in humans of approximately 664 -2380 days and 64 days for PBDEs and HBCDD, respectively (Geyer et al, 2004), and have been associated with adverse health effects in humans.. For example, PBDEs are thought to disrupt levels of sex hormones, including luteinising hormone and follicle stimulating hormone in men (Meeker et al, 2009), in addition to other toxic effects including disruption to the liver, kidneys and thyroid gland; neurodevelopmental deficits including inhibited foetal and infant development; and various cancers (Costa, 2008). Furthermore, in vitro studies have demonstrated that doses as low as 5µM can induce oxidative stress and disrupt steroidogenesis, with high level PBDE exposure resulting in pregnancy failure (Lefevre et al, 2016). Exposure to the Penta-BDE formulation can activate the aryl hydrocarbon (Ah) -receptor (Gu et al, 2012), cause a reduction in hepatic vitamin A levels, impair neurodevelopment, and induce carcinogenesis (D'Silva et al, 2004, Hornung et al, 1996.…”