Influence of aryl hydrocarbon receptor and sulfotransferase 1A1 on bisphenol AF-induced clastogenesis in human hepatoma cells. (15th April 2022)

• Record Type: Journal Article
• Authors: Yang, Zongying; Yu, Hang; Tu, Hongwei; Chen, Zhihong; Hu, Keqi; Jia, Hansi; Liu, Yungang
• Is Part Of: Toxicology. Volume 471(2022)
• Publication Date: 2022-04-15
• Subjects: ABT 1-Aminobenzotriazole -- AhR Aryl hydrocarbon receptor -- ANOVA Analysis of variance -- ATCC American Type Culture Collection -- BaP Benzo(a)pyrene -- BP Bisphenol -- CCK Cell counting kit -- CENP-B Centromere protein B -- CYP Cytochrome P450 -- DMSO Dimethylsulfoxide -- EMS Ethyl methanesulfonate -- FBS Fetal bovine serum -- GAPDH Glyceraldehyde-3-phosphate dehydrogenase -- HF 7-Hydroxyflavone -- 1-HMP 1-Hydroxymethylpyrene -- PC Polycarbonate -- PCB Polychlorinated biphenyl -- PCR Polymerase chain reaction -- ROS Reactive oxygen species -- RT Reverse transcription -- SDS Sodium dodecyl sulfate -- SULTs Sulfotransferases -- TCDD 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin -- TCDF 2, 3, 7, 8-tetradibenzofuran -- VCR Vincristine -- UGTs UDP-glucuronosyl transferases; Aryl hydrocarbon receptor (AhR) -- Bisphenol AF -- Centromere protein B -- CYP1A1 -- Micronuclei -- Sulfotransferase; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2022.153175
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: Bisphenol compounds (BPs) are ubiquitously existing pollutants. Recent evidence shows that they may be activated by human CYP1A1 for clastogenic effects; however, factors that influence/mediate CYP1A1-activated 4, 4′-(hexafluoroisopropylidene)diphenol (BPAF) toxicity, particularly the aryl hydrocarbon receptor (AhR), sulfotransferase (SULT) 1A1 [known to conjugate 2, 2-bis(4-hydroxyphenol)-propane (BPA)] and reactive oxygen species (ROS), remain unclear. In this study, a human hepatoma (HepG2) cell line was genetically engineered for the expression of human CYP1A1 and SULT1A1, producing HepG2-hCYP1A1 and HepG2-hSULT1A1, respectively. They were used in the micronucleus test and γ-H2AX analysis (Western blot) (indicating double-strand DNA breaks) with BPAF; the role of AhR in mediating BPAF toxicity was investigated by coexposure of AhR modulators in HepG2 and its derivative C3A (with no genetic modifications but enhanced CYP expression). The results indicated induction of micronuclei by BPAF (≥ 2.5 µM, for 2-cell cycle) in HepG2-hCYP1A1 and C3A, while inactive in HepG2 and HepG2-hSULT1A1; however, BPAF induced micronuclei in HepG2 pretreated with 3, 3′, 4, 4′, 5-pentachlorobiphenyl (PCB126, AhR activator), and BAY-218 (AhR inhibitor) blocked the effect of BPAF in C3A. In HepG2-hCYP1A1 BPAF selectively induced centromere-free micronuclei (immunofluorescent assay) and double-strand DNA breaks. In HepG2 cells receiving conditional medium from BPAF-HepG2-hCYP1A1 incubation micronuclei were formed, while negative in HepG2-hSULT1A1. Finally, the intracellular levels of ROS, superoxide dismutase and reduced glutathione in C3A and HepG2-hCYP1A1 exposed to BPAF were all moderately increased, while unchanged in HepG2 cells. In conclusion, like other BPs BPAF is activated by human CYP1A1 for potent clastogenicity, and this effect is enhanced by AhR while alleviated by SULT1A1. Graphical Abstract: ga1 Highlights: Bisphenol AF (BPAF) induces chromosome/DNA breaks in human cells. BPAF is activated by human CYP1A1 while detoxified by SULT1A1. Activation of aromatic hydrocarbon receptor enhances genotoxicity of BPAF. Reactive oxygen species seems insignificant in CYP1A1-activated BPAF genotoxicity.