Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, H3G 1Y6, Canada.
Existing Substances Risk Assessment Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, K1A 0K9, Canada.
Toxicol Sci. 2021 Apr 12;180(2):224-238. doi: 10.1093/toxsci/kfab012.
Concerns about the potential adverse effects of bisphenol A (BPA) have led to an increase in the use of replacements, yet the toxicity data for several of these chemicals are limited. Using high-content imaging, we compared the effects of BPA, BPAF, BPF, BPS, BPM, and BPTMC in germ (C18-4 spermatogonial) and steroidogenic (MA-10 Leydig and KGN granulosa) cell lines. Effects on cell viability and phenotypic markers were analyzed to determine benchmark concentrations (BMCs) and estimate administered equivalent doses (AEDs). In all 3 cell lines, BPA was one of the least cytotoxic bisphenol compounds tested, whereas BPM and BPTMC were the most cytotoxic. Interestingly, BPF and BPS were cytotoxic only in MA-10 cells. Effects on phenotypic parameters, including mitochondria, lysosomes, lipid droplets, and oxidative stress, were both bisphenol- and cell-line specific. BPA exposure affected mitochondria (BMC: 1.2 μM; AED: 0.09 mg/kg/day) in C18-4 cells. Lysosome numbers were increased in MA-10 cells exposed to BPA or BPAF but decreased in KGN cells exposed to BPAF or BPM. Lipid droplets were decreased in C18-4 cells exposed to BPF and in MA-10 cells exposed to BPTMC but increased in BPF, BPM, and BPTMC-exposed KGN cells. BPA and BPM exposure induced oxidative stress in MA-10 and KGN cells, respectively. In summary, structurally similar bisphenols displayed clear cell-line-specific differences in BMC and AED values for effects on cell viability and phenotypic endpoints. This approach, together with additional data on human exposure, may aid in the selection and prioritization of responsible replacements for BPA. .
人们对双酚 A（BPA）潜在的不良影响感到担忧，这导致了其替代品的使用增加，但这些化学物质的毒性数据有限。本研究使用高内涵成像技术，比较了 BPA、BPAF、BPF、BPS、BPM 和 BPTMC 对生殖（C18-4 精原）和类固醇生成（MA-10 间质和 KGN 颗粒）细胞系的影响。分析了细胞活力和表型标志物的变化，以确定基准浓度（BMCs）并估计给药等效剂量（AEDs）。在所有 3 种细胞系中，BPA 是测试的最不易细胞毒性的双酚化合物之一，而 BPM 和 BPTMC 是最具细胞毒性的。有趣的是，BPF 和 BPS 仅在 MA-10 细胞中具有细胞毒性。对表型参数的影响，包括线粒体、溶酶体、脂滴和氧化应激，均具有双酚和细胞系特异性。BPA 暴露影响 C18-4 细胞的线粒体（BMC：1.2 μM；AED：0.09 mg/kg/天）。BPA 或 BPAF 暴露会增加 MA-10 细胞中的溶酶体数量，但 BPAF 或 BPM 暴露会减少 KGN 细胞中的溶酶体数量。BPF 暴露会减少 C18-4 细胞中的脂滴，BPTMC 暴露会减少 MA-10 细胞中的脂滴，但 BPF、BPM 和 BPTMC 暴露会增加 KGN 细胞中的脂滴。BPA 和 BPM 暴露分别诱导 MA-10 和 KGN 细胞的氧化应激。总之，结构相似的双酚表现出明显的细胞系特异性差异，表现在对细胞活力和表型终点的 BMC 和 AED 值上。这种方法，结合关于人类暴露的其他数据，可能有助于选择和优先考虑对 BPA 负责的替代品。
