title: High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells.
abstract: Bisphenol A (BPA), an endocrine-disrupting compound, was found to be a testicular toxicant in animal models. Bisphenol S (BPS), bisphenol AF (BPAF), and tetrabromobisphenol A (TBBPA) were recently introduced to the market as alternatives to BPA. However, toxicological data of these compounds in the male reproductive system are still limited so far. This study developed and validated an automated multi-parametric high-content analysis (HCA) using the C18-4 spermatogonial cell line as a model. We applied these validated HCA, including nuclear morphology, DNA content, cell cycle progression, DNA synthesis, cytoskeleton integrity, and DNA damage responses, to characterize and compare the testicular toxicities of BPA and 3 selected commercial available BPA analogues, BPS, BPAF, and TBBPA. HCA revealed BPAF and TBBPA exhibited higher spermatogonial toxicities as compared with BPA and BPS, including dose- and time-dependent alterations in nuclear morphology, cell cycle, DNA damage responses, and perturbation of the cytoskeleton. Our results demonstrated that this specific culture model together with HCA can be utilized for quantitative screening and discriminating of chemical-specific testicular toxicity in spermatogonial cells. It also provides a fast and cost-effective approach for the identification of environmental chemicals that could have detrimental effects on reproduction.
authors.affiliation: Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, Georgia.
authors.forename: Shenxuan
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, Georgia.|ReproTox Biotech LLC, 111 Riverbend Drive, Athens, Georgia.
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, Georgia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shengyang Yu
authors.affiliation: Department of Endocrine Neoplasia & Hormonal Disorders, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit no. 1105 Houston, Texas.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Hofmann
authors.affiliation: Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, Georgia; yuxz@uga.edu.
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Yu
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010636:Phenols / Q000633:toxicity*; D013093:Spermatogonia / Q000187:drug effects*; D013737:Testis / Q000166:cytology / Q000187:drug effects*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: C18-4 spermatogonial cell line; DNA damage responses; and tetrabromobisphenol A; bisphenol A; bisphenol AF; bisphenol S; cell cycle; cytoskeleton.; high-content analysis