Cytochrome P450 3A1 Mediates 2,2′,4,4′-Tetrabromodiphenyl Ether-Induced Reduction of Spermatogenesis in Adult Rats

Abstract

Background2,2′,4,4′-tetrabromodiphenyl ether (BDE47) is the dominant PBDE congener in humans, wildlife, and the environment. It has been reported to be metabolized by cytochrome P450 (CYP) enzymes. Still, the effects of BDE47 on spermatogenesis failure are attracting an increasing amount of attention. However, it is unclear whether CYP-mediated metabolism contributes to BDE47-induced reproductive toxicity.Methodology and Principal FindingsThe role of cytochrome P450 3A1 (CYP3A1) in the formation of oxidative metabolites of BDE47 and its induced spermatogenesis failure was investigated in SD rats. BDE47 significantly increased the expression and activity of CYP3A1 in rat liver, and 3-OH-BDE47, the major oxidative metabolite of BDE47, dose-dependently increased in rat liver, serum, and testis, which was aggravated by dexamethasone (DEX), an inducer of CYP3A1. Additionally, testicular 3-OH-BDE47 and reactive oxygen species (ROS) in seminiferous tubules increased especially when BDE47 was administered in combination with DEX, which was confirmed in GC-1 and GC-2 cells that 3-OH-BDE47 induced more ROS production and cell apoptosis via the upregulation of FAS/FASL, p-p53 and caspase 3. As a result, daily sperm production dose-dependently decreased, consistent with histological observations in giant cells and vacuolar spaces and increase in TUNEL-positive apoptotic germ cells.ConclusionCYP3A1-mediated metabolic activation of BDE47 and the active metabolite 3-OH-BDE47 and consequent ROS played an important role in reduction of spermatogenesis by germ cell apoptosis. Our study helps provide new insights into the mechanism of reproductive toxicity of environmental chemicals.

2,2′,4,4′-Tetrabromodiphenyl ether disrupts spermatogenesis, impairs mitochondrial function and induces apoptosis of early leptotene spermatocytes in rats

“…Data showed a gradual reduction in relative epithelial thickness (Fig. 1A), consistent with the gradual impaired spermatogenesis in our previous study [16]. Previous studies reported that BDE47 induced apoptosis in the hematopoietic stem cells [13].…”

“…Our previous study demonstrated that BDE47 dose-dependently reduced the spermatogenesis, induced reactive oxygen species (ROS) and apoptosis of spermatocytes in rat testis. But the testis proteomics changes effected by low-dose BDE47 related to impaired spermatogenesis are still unknown [16]. Also, as to the spermatocytes, include several developmental stages such as leptotene, zygotene, pachytene, diplotene and diakinesis [32].…”

“…Our previous study demonstrated that BDE47 dose-dependently reduced the spermatogenesis, induced apoptosis of spermatocytes and reactive oxygen species (ROS) in seminiferous tubules. Also, BDE47 induced apoptosis related proteins FAS/FASL, p-p53 and caspase 3 in rat testis [16]. But what kind of the molecular markers that are related to impaired spermatogenesis effected by BDE47 are still unknown.…”

Differential nanoreprotoxicity of silver nanoparticles in male somatic cells and spermatogonial stem cells

“…Oxidative stress can strongly affect testicular functions important for spermatogenesis. 29 Reactive oxygen species (ROS) are generated either by the mitochondrial electron transport chain or by nicotinamide adenine dinucleotide phosphate oxidase. 30 Mitochondrial-derived ROS have been implicated in a number of diseases and are known to cause cell and tissue destruction through DNA damage, lipid peroxidation, protein oxidation, and carbonylation, depletion of cellular thiols, and activation of proinflammatory cytokine release.…”

Characterization of the molecular degradation mechanism of diphenyl ethers by Cupriavidus sp. WS

“…L o n g -t e r m e x p o s u r e t o P B D E s c a n c a u s e neurodevelopmental toxicity, as well as endocrine disruption in mammals (Napoli et al 2013;Nash et al 2013;Ren and Guo 2013;Zhang et al 2013). Thus, efforts have intensified during recent decades to eliminate PBDEs from the environment.…”