Department of Biotechnology and Cell Biology, Medical College, University of Information Technology and Management in Rzeszow, Sucharskiego 2, 35-225, Rzeszów, Poland.
Department of Biopharmacy, Medical University of Lublin, Chodźki 4a, 20-093, Lublin, Poland.
Chemosphere. 2024 Sep;363:142802. doi: 10.1016/j.chemosphere.2024.142802. Epub 2024 Jul 10.
The decline in male reproductive health, characterized by diminishing sperm count and testosterone levels, has raised concerns about environmental influences, particularly endocrine-disrupting chemicals (EDCs). Tris(2,3-dibromopropyl)isocyanurate (TBC), a novel brominated flame retardant widely used in electronics, textiles, and furniture, has emerged as a significant environmental contaminant with potential reproductive health implications. In this study, we investigated the molecular mechanisms underlying TBC-induced reproductive toxicity, particularly focusing on its impact on steroidogenesis and androgen signaling pathways using the GC-1 spg cell line as an in vitro model. Exposure of GC-1 spg cells to TBC, alone or in combination with testosterone or the anti-androgen flutamide resulted in decreased metabolic activity and increased lactate dehydrogenase release, indicating cytotoxic effects. Furthermore, TBC exposure led to a reduction in progesterone synthesis, while testosterone production remained unaffected. Interestingly, estradiol synthesis was diminished after TBC exposure, suggesting a disruption in steroid hormone balance critical for spermatogenesis. Mechanistic investigations revealed alterations in key proteins involved in the non-classical testosterone pathway and steroidogenesis. TBC exposure downregulated epidermal growth factor receptor (EGFR), protein kinase B (AKT), and phosphorylated cyclic AMP response element-binding protein (p-CREB), indicating suppression of non-classical androgen signaling. Additionally, decreased levels of steroidogenic acute regulatory protein (StAR) and 3-beta-hydroxysteroid dehydrogenase (HSD3β1) suggest impaired steroidogenesis. Here we uncover the intricate molecular mechanisms underlying TBC-induced reproductive toxicity, highlighting its potential to disrupt steroid hormone synthesis and androgen signaling pathways. Understanding the adverse effects of TBC on male reproductive health is crucial for developing strategies to mitigate its environmental impact and safeguard human fertility.
男性生殖健康的下降，表现为精子数量和睾酮水平的降低，引起了人们对环境影响的关注，特别是内分泌干扰化学物质（EDCs）。三（2,3-二溴丙基）异氰尿酸酯（TBC）是一种新型溴化阻燃剂，广泛应用于电子、纺织品和家具中，已成为一种具有潜在生殖健康影响的重要环境污染物。在这项研究中，我们研究了 TBC 诱导生殖毒性的分子机制，特别是关注了它对类固醇生成和雄激素信号通路的影响，使用 GC-1 spg 细胞系作为体外模型。GC-1 spg 细胞单独或与睾酮或抗雄激素氟他胺一起暴露于 TBC 中，会导致代谢活性降低和乳酸脱氢酶释放增加，表明存在细胞毒性。此外，TBC 暴露会导致孕激素合成减少，而睾酮生成不受影响。有趣的是，TBC 暴露后雌二醇合成减少，表明类固醇激素平衡受到干扰，这对精子发生至关重要。机制研究揭示了参与非经典睾酮途径和类固醇生成的关键蛋白的改变。TBC 暴露下调表皮生长因子受体（EGFR）、蛋白激酶 B（AKT）和磷酸化环 AMP 反应元件结合蛋白（p-CREB），表明非经典雄激素信号受到抑制。此外，类固醇生成急性调节蛋白（StAR）和 3-β-羟甾脱氢酶（HSD3β1）的水平降低表明类固醇生成受损。在这里，我们揭示了 TBC 诱导生殖毒性的复杂分子机制，强调了它对类固醇激素合成和雄激素信号通路的潜在干扰作用。了解 TBC 对男性生殖健康的不良影响对于制定减轻其环境影响和保护人类生育能力的策略至关重要。
