Integrated Proteomic and Metabolomic Analysis of the Testes Characterizes BDE-47-Induced Reproductive Toxicity in Mice

Abstract

A representative congener of polybrominated diphenyl ethers in the environment, 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), is associated with male reproductive toxicity, yet the underlying mechanisms remain largely unclear. In this study, mice were administered environmentally relevant concentrations of BDE-47 for six weeks. Histopathological observations showed that BDE-47 induced inflammatory reactions and damaged the testes. By conducting an integrated proteomic and metabolomic analysis coupled with a bioinformatic analysis using ingenuity pathway analysis (IPA) methods, we found that BDE-47 mainly affected the molecules involved in free radical scavenging, cell death and survival, neurological disease, and inflammatory response. IPA canonical pathways showed inflammatory and apoptosis pathways, including hepatic fibrosis/hepatic stellate cell activation, the GP6 signaling pathway, tight junction signaling, acute phase response signaling, LXR/RXR activation, unfolded protein response, and FXR/RXR activation, which are related to male reproductive toxicity. Key transcriptional regulator networks were activated via a focus on upstream regulator analysis. The expression of MYC and Clu as the core transcriptional factor and targeted protein, respectively, was verified. It is further proposed that MYC may contribute to the etiology of male reproductive toxicity. These findings will improve our understanding of the mechanisms responsible for BDE-47-induced male reproductive toxicity, which may promote the discovery of useful biomarkers indicative of BDE-47 exposure.

Mechanisms of Male Reproductive Toxicity of Polybrominated Diphenyl Ethers

“…No significant difference between sperm morphology of exposed and control groups was observed in this study; however, some sperm motility parameters were impaired in some exposed groups. In another BDE-47 study, histopathological examination of mice exposed to 1.5, 10, and 30 mg/kg of BDE-47 for six weeks showed sperm decrease in the epididymal lumen at 10 and 30 mg/kg [46].…”

“…In another study, suppurative inflammation of the epididymis in mice was observed after exposure to 30 mg/kg of BDE-47 for 6 weeks [46]. Additionally proteomic and metabolomic analysis of testis tissue showed that BDE-47 can trigger the apoptosis and inflammatory pathway [46]. However, this analysis was done for a merged list of proteins and metabolites affected by either dose used in the study: 1.5, 10, and 30 mg/kg/day daily for 6 weeks.…”

“…For instance, inflammatory cell infiltration was observed in the epididymis interstitium of mice dosed with 30 mg/kg/BW of BDE-3 [47]. In another study, suppurative inflammation of the epididymis in mice was observed after exposure to 30 mg/kg of BDE-47 for 6 weeks [46]. Additionally proteomic and metabolomic analysis of testis tissue showed that BDE-47 can trigger the apoptosis and inflammatory pathway [46].…”

“…A growing body of literature provides clear evidence that early life exposures to PBDEs at environmentally relevant doses may have long-lasting effects on mammalian tissue physiology [93,94,116,117], including male reproductive tissues [33,34,40,43,114]. Studies demonstrate that perinatal or neonatal exposures result in reduced testis weight and reduced sperm quality parameters [33,34,43,46,114].…”

Metabolomics insights into the prenatal exposure effects of polybrominated diphenyl ethers on neonatal birth outcomes

“…Metabolomics, as a sensitive barometer of external stimulation and pathological insults, provides a powerful strategy for screening environmental exposures-related and adverse outcomes-related metabolites with no prior hypothesis and contributes to the characterization of their complicated mechanisms from a metabolic perspective (Huang et al, 2018;Valvi et al, 2020;You et al, 2021). To date, some metabolomics studies on PBDE exposure effects have addressed the compelling metabolic changes in the animal and cell lines models (Chi et al, 2011;Ji et al, 2019a;Tang et al, 2019;Wei et al, 2018;Xu et al, 2021;Yang et al, 2019), concerning on breast cancer (Wei et al, 2018), hepatic steatosis (Yang et al, 2019), neurotoxicity (Ji et al, 2019a;Tang et al, 2019), reproductive toxicity (Xu et al, 2021) and embryo-toxicity (Chi et al, 2011). In addition, a few studies have used metabolomics approach to investigate the underlying metabolism disorders of adverse pregnancy outcomes, such as intrauterine growth restriction (IUGR) (Favretto et al, 2012) and spontaneous preterm birth (SPB) (Elshenawy et al, 2020).…”