Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China.
Ecotoxicol Environ Saf. 2021 Jun 1;215:112136. doi: 10.1016/j.ecoenv.2021.112136. Epub 2021 Mar 15.
The combined toxicological assessment provides a realistic approach for hazard evaluation of chemical cocktails that co-existed in the environment. This review provides a holistic insight into the studies highlighting the mixture toxicity of the endocrine-disrupting chemicals (EDCs), especially focusing on the screening of biochemical pathways and other toxicogenetic endpoints. Reviewed literature showed that numerous multiplexed toxicogenomic techniques were applied to determine reproductive effects in vertebrates, but limited studies were found in non-mammalian species after mixture chemical exposure. Further, we found that the experimental design and concentration selection are the two important parameters in mixture toxicity studies that should be time- and cost-effective, highly precise, and environmentally relevant. A summary of EDC mixtures affecting the thyroid axis, estrogen axis, androgen axis, growth stress, and immune system via in vivo bioassays was also presented. It is interesting to mention that majority of estrogenic effects of the mixtures were sex-dependent, particularly observed in male fish as compared to female fish. Further, the androgen axis was perturbed with serious malformations in male rat testis (epididymal or gubernacular lesions, and deciduous spermatids). Also, transgenerational epigenetic effects were promoted in the F and F generations in the form of DNA methylation epimutations in sperm, increasing polycystic ovaries and reducing the offspring. Similarly, increased oxidative stress, high antioxidant enzymatic activities, disturbed estrous cycle, and decreased steroidogenesis were the commonly found effects after acute or chronic exposure to EDC mixtures. Importantly, the concentration addition (CA) and independent action (IA) models became more prevalent and suitable predictive models to unveil the prominence of synergistic estrogenic and anti-androgenic effects of chemical mixtures. More importantly, this review encompasses the research challenges and gaps in the existing knowledge and specific future research perspectives on combined toxicity.
联合毒理学评估为评估环境中共存的化学混合物的危害提供了一种现实的方法。本综述全面了解了强调内分泌干扰化学物质（EDCs）混合物毒性的研究，特别是侧重于生化途径和其他毒遗传学终点的筛选。综述文献表明，许多多重毒代基因组学技术已应用于确定脊椎动物的生殖毒性，但在混合物化学暴露后，在非哺乳动物物种中发现的研究有限。此外，我们发现实验设计和浓度选择是混合物毒性研究中的两个重要参数，应具有时间和成本效益、高度精确性和与环境的相关性。还介绍了通过体内生物测定法影响甲状腺轴、雌激素轴、雄激素轴、生长应激和免疫系统的 EDC 混合物的摘要。有趣的是，要提到的是，混合物的大多数雌激素效应是性别依赖性的，特别是与雌性鱼类相比，在雄性鱼类中观察到。此外，雄激素轴受到严重畸形的干扰，雄性大鼠睾丸（附睾或 gubernacular 病变，以及退化精子）。同样，以精子中的 DNA 甲基化表突变形式在 F 和 F 代中促进了跨代表观遗传效应，增加了多囊卵巢并减少了后代。同样，在急性或慢性暴露于 EDC 混合物后，通常会发现氧化应激增加、抗氧化酶活性升高、发情周期紊乱和类固醇生成减少。重要的是，浓度加和（CA）和独立作用（IA）模型变得更加流行和适合预测模型，以揭示化学混合物协同雌激素和抗雄激素作用的重要性。更重要的是，本综述涵盖了现有知识中的研究挑战和差距以及联合毒性的具体未来研究展望。
