BDE-209 exposure induced male reproductive toxicity with sperm quality decline. However, the role of autophagy in this was unclear. The purpose was to evaluate the protective effect and its potential mechanism of trehalose (Tre, autophagy inducer) on reproductive damage during spermiogenesis induced by BDE-209. We used 2% w/v Tre and 75 mg/kg/d BDE-209 cotreated mice for 42 days. GC-2 spd cells were cotreated with Tre, chloroquine (CQ, inhibition of autophagic flux), compound C (CC, AMPK inhibitor), and BDE-209. Tre intake significantly recovered decrease in sexual organ ratio and poor sperm quality in BDE-209-exposed mice. Supplementation with Tre rescued sperm head malformation by improving aberrant histone-protamine exchange in BDE-209-exposed mice. However, Tre intake couldn't restore the acrosome biogenesis. In addition, Tre supplementation improved testicular damage induced by BDE-209. BDE-209 blocked autophagic flux with increased P62 and LC3BII/I levels. Mechanistically, CQ treatment aggravated elevation of P62 and LC3BII/I levels induced by BDE-209, otherwise, CC and Tre treatments inhibited the rise in p-AMPK, p-ULK1, P62 and LC3BII/I levels induced by BDE-209. Tre supplementation improved reproductive injury in BDE-209-exposed mice by regulating autophagic flow via AMPK-ULK1 signaling pathways, which providing a new theoretical basis and possible therapeutic targets for male reproductive toxicity.

Deca-bromodiphenyl ethers (BDE-209) has been widely used in electronic devices and textiles as additives to flame retardants. Growing evidence showed that BDE-209 exposure leads to poorer sperm quality and male reproductive dysfunction. However, the underlying mechanisms of BDE-209 exposure caused a decline in sperm quality remains unclear. This study aimed to evaluate the protective effects of N-acetylcysteine (NAC) on meiotic arrest in spermatocytes and decreased sperm quality in BDE-209-exposed mice. In the study, mice were treated with NAC (150 mg/kg BW) 2 h before administrated with BDE-209 (80 mg/kg BW) for 2 weeks. For the in vitro studies, spermatocyte cell line GC-2spd cells were pretreated with NAC (5 mM) 2 h before treated with BDE-209 (50 μM) for 24 h. We found that pretreatment with NAC attenuated the oxidative stress status induced by BDE-209 in vivo and in vitro. Moreover, pretreatment with NAC rescued the testicular histology impairment and decreased the testicular organ coefficient in BDE-209-exposed mice. In addition, NAC supplement partially promoted meiotic prophase and improved sperm quality in BDE-209-exposed mice. Furthermore, NAC pretreatment effectively improved DNA damage repair by recovering DMC1, RAD51, and MLH1. In conclusion, BDE-209 caused spermatogenesis dysfunction related to the meiotic arrest medicated by oxidative stress, decreasing sperm quality.

Deca brominated diphenyl ether (BDE-209) is a widely used flame retardant with endocrine-disrupting activity which reportedly caused sperm quality decline and damaged blood-testis barrier (BTB). However, whether BDE-209 exposure led to BTB integrity dysfunction through affecting microtubule cytoskeletal organization and junctions was not well-elucidated. This study aimed to investigate the role of estrogen receptor α (ERα) in BDE-209-mediated perturbation of BTB integrity. Male rats and primary culture Sertoli cells were co-treated with BDE-209 and propylpyrazoletriol (PPT). The data demonstrated that BDE-209 impaired BTB integrity by reducing crucial tight junction-related proteins with ZO-1 and Occludin. Furthermore, the data suggested that BDE-209 diminished the apical ectoplasmic specialization markers with Eps8 and Formin1. In addition, BDE-209 damaged BTB ultrastructure including tight junctions and ectoplasmic specialization structures with broken tight junctions and the absence of actin microfilaments. Further experiments revealed that ERα was triggered in BDE-209-treated Sertoli cells. Unexpectedly, we found that PPT rescued BDE-209-mediated disruption of BTB integrity including tight junction and apical ectoplasmic specialization by activating ERα in Sertoli cells. Taken together, these findings indicated that intratesticular BDE-209 exposure perturbed BTB integrity and destroyed BTB structure by blocking ERα pathway. Our findings provide a new therapeutic target for male reproductive dysfunction.

Deca-bromodiphenyl ether (BDE-209) exposure caused spermatogenesis disorder resulting in poor sperm quality has become a public concern in recent years. Spermatogenesis refers to the process by which the division of spermatogonia stem cells (SSCs) produces haploid spermatozoa, including mitosis, meiosis, and spermiogenesis. However, the mechanism of mitosis including proliferation and differentiation of spermatogonia dysfunction induced by BDE-209 remains largely unclear. Here, our data showed that BDE-209 exposure caused a decline in sperm quality with seminiferous tubule structure disorder in rats. In addition, BDE-209 exposure damage spermatogonia proliferation and differentiation with decreasing level of PLZF and cKit in testis. Moreover, rats exposed to BDE-209 decreased the expression of ERα, whereas an elevated expression of Wnt3a and Wnt5a. Mechanistically, supplementation with propipyrazole triol (PPT, a selective ERα pathway agonist) rescued sperm quality and attenuated impairment of proliferation and differentiation of spermatogonia in BDE-209-induced rats. Therefore, ERα plays a crucial role in the proliferation and differentiation of spermatogonia during mitotic process. In conclusion, our study clarified the role of ERα in BDE-209-induced spermatogonia proliferation and differentiation in rats and provides a potential therapeutic application on poor sperm quality caused by BDE-209 exposure.

Deca-brominated diphenyl ether (BDE-209) is a common flame retardant utilized in electronic products, textiles, furniture, and upholstery materials. Environmental BDE-209 exposure results in spermatogenesis disorder, because of the characteristics of bioaccumulation, persistence, and probably toxicity. Meiotic prophase I is a crucial phase during spermatogenesis which is a key influential factor of normal sperm production. However, the effects of BDE-209 on meiotic prophase I during spermatogenesis are poorly understood. The present study aimed to evaluate whether BDE-209 exposure impairs meiotic prophase I during spermatogenesis of spermatocytes. We validated the effects of BDE-209 on alternations of meiotic prophase I in Balb/c male mice. Firstly, we analyzed sperm quality in cauda epididymis with decreasing sperm count, increasing abnormal sperm, and male reproductive dysfunction after exposure to BDE-209. Then, reactive oxygen species (ROS) and malondialdehyde (MDA) levels in testis and GC-2spd cells were significant increased after treated with BDE-209. Furthermore, we found that meiotic prophase I arrest at early-pachytene stage during spermatogenesis with increasing of DSBs damage and trimethylated histone H3 at lysine-4 (H3K4me3) in spermatocytes exposed to BDE-209. Finally, we conducted homologous recombination (HR) analyses to identify the progression of meiosis. The recombination markers, including DMC1 and RAD51, and crossover marker MLH1 were decreased during spermatogenesis after exposure to BDE-209. Collectively, our data indicated that BDE-209 has detrimental impacts on meiotic prophase I of spermatocytes in mice.

A systematic review and meta-analysis were conducted to understand the association of phthalates and their metabolites with sperm quality in humans. By June 30, 2022, relevant literature on the effects of phthalates and their metabolites on sperm quality were searched and collected using three English-language databases including PubMed, EMbase, and Web of Science. Two researchers independently screened literature, extracted data, and assessed risk of bias. Stata 11 and RevMan 5.3 were used to conduct meta-analysis, test publication bias, and sensitivity analysis. A total of 12 literature were included for meta-analysis, excluding literature with different effect sizes. The results of meta-analysis indicated that monobutyl phthalate (MBP) and monobenzyl phthalate (MBzP) in urine were negatively correlated with semen concentration, and the results were statistically significant (MBP, pooled odds ratio (OR), 95% confidence interval (CI): 2.186 (1.471, 3.248), P < 0.05) and ( MBzP, pooled OR (95%CI): 1.882 (1.471, 3.248), P < 0.05). Furthermore, the level of Di-(2-ethylhexyl) phthalate (DEHP) in semen was negatively correlated with semen concentration and the combined effect size was (pooled correlation coefficients (r) (95%CI): -0.225 (-0.319, -0.192), P < 0.05). However, the associations between MBP and MBzP with sperm motility and sperm morphology were not statistically significant (P > 0.05). And there was also no significant correlation between monoethyl phthalate (MEP), monomethyl phthalate (MMP), and mono-2-ethylhexyl phthalate (MEHP) and semen parameters, including semen concentration, sperm motility, and sperm morphology (P > 0.05). In summary, this current study provides moderate-certainty evidence for the data demonstrated that is a negative correlation between urine MBP levels, urine MBzP levels, and semen DEHP levels with semen concentration. In the future, more longitudinal cohort studies are needed to help elucidate the overall association.

Deca-brominated diphenyl ether (BDE-209) is a ubiquitous industrial chemical as brominated flame retardant (BFRs). Exposure to BDE-209 has been clearly associated with male reproductive disorders. However, the meiotic arrest mechanism of spermatocytes exposed to BDE-209 is still unclear. The present work aimed to explore the protective effect of vitamin C on BDE-209-induced meiotic arrest of spermatocytes and its possible mechanism. Vitamin C (100 mg/kg BW) was administered to BDE-209-exposed (80 mg/kg BW) male Balb/c mice once daily by intraperitoneal injection for 2 weeks. Our results showed that vitamin C played male reproductive protection effects as showed by attenuated BDE-209-induced testicular damage, and reduced sperm abnormality rate. Vitamin C also attenuated BDE-209-induced increase in SOD and MDA in testes and GC-2 spd cells. Moreover, vitamin C promoted meiotic prophase in BDE-209-induced mice, with suppressed γ-H2AX, restored DMC1, RAD51, and crossover marker MLH1 levels, and prevented BDE-209-induced DNA impairment. In addition, vitamin C supplementation also interfered with BDE-209-induced upregulation of testicular H3K4me3 through inhibition of KDM5s capacity and decreasing ferrous ion concentration. Furthermore, ferrous sulfate pretreatment could partially restore the expression of H3K4me3 via maintaining the concentration of ferrous ions. Taken together, vitamin C exerts a potential therapeutic agent for preventing BDE-209-induced reproductive toxicity with meiotic arrest, which is attributed to its antioxidant and electron donor properties, as well as, modulation of ferrous ion levels and demethylation of H3K4me3.

To explore the relationship between perinatal exposure to endocrine-disrupting chemicals and the male reproductive system of F3 generation, and to evaluate the toxicological effects of endocrine-disrupting chemicals on the reproductive system of F3 generation male rodents. PubMed and Web of Science databases were searched to obtain the studies; overall risk ratios (RRs) with 95% confidence intervals (95% CIs) were used to evaluate the relationship between exposure to endocrine-disrupting chemicals and reproductive system damage in F3 generation male rodents. Nine studies were included for analysis. Endocrine-disrupting chemicals are significantly associated with the reproductive system of male rodents of F3 generation, especially the testis (RR = 3.13, 95% CI: 2.05, 4.76), prostate (RR = 2.26, 95% CI: 1.27, 4.00), and kidney (RR = 2.83, 95% CI: 1.77, 4.52), but the current analysis does not prove that EDCs are the adverse factors for puberty abnormalities. The results indicated that the overall associations between atrazine (RR = 3.06, 95% CI: 1.10, 8.51, P = 0.032), DDT (RR = 6.26, 95% CI: 1.56, 25.08, P = 0.010), pesticide and insect repellent mixture (permethrin and DEET) (RR = 2.23, 95% CI: 1.34, 3.69, P = 0.002), and vinclozolin (RR = 4.71, 95% CI: 2.74, 8.10, P = 0.000) and reproductive system damage in F3 generation male rodents were statistically significant. Our study indicated that EDCs have an atavistic effect on the male reproductive system, and we should pay attention to the long-term effects of environmental exposure to endocrine disruptors in future generations.