3,3 '-Dichlorobiphenyl Is Metabolized to a Complex Mixture of Oxidative Metabolites, Including Novel Methoxylated Metabolites, by HepG2 Cells

• Type of Material: Article
• Authors: Chun-Yun Zhang, University of Iowa; Susanne Flor, University of Iowa; Patricia Ruiz, Agency for Toxic Substances and Disease Registry, Atlanta; Ram Dhakal, University of Iowa; Xin Hu, Emory University; Lynn M Teesch, University of Iowa; Gabriele Ludewig, University of Iowa; Hans-Joachim Lehmler, University of Iowa
• Language: English
• Date: 2020-10-06
• Publisher: AMER CHEMICAL SOC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 American Chemical Society
• Final Published Version (URL): http://dx.doi.org/10.1021/acs.est.0c03476
• Title of Journal or Parent Work: ENVIRONMENTAL SCIENCE & TECHNOLOGY
• Volume: 54
• Issue: 19
• Start Page: 12345
• End Page: 12357
• Grant/Funding Information: This work was supported by grants ES027169 [HJL], ES019776 [XL], ES014901 [HJL], ES013661[HJL, GL], and ES005605 [HJL] from the National Institute of Environmental Health Sciences, National Institutes of Health. The content is solely the responsibility of the authors. It does not necessarily represent the official views of the National Institute of Environmental Health Sciences/National Institutes of Health. The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry and should not be construed to represent any agency determination or policy.
• Keywords: GREAT-LAKES; SULFATED METABOLITES; Environmental Sciences & Ecology; HUMAN SERUM; HYDROXYLATED POLYCHLORINATED-BIPHENYLS; INHALATION EXPOSURE; Engineering; HUMAN HEPATOCYTES; NON-AROCLOR; Engineering, Environmental; HEPATIC-METABOLISM; Science & Technology; IN-VITRO; 4-CHLOROBIPHENYL PCB3; Environmental Sciences; Technology; Life Sciences & Biomedicine

Abstract

3,3′-Dichlorobiphenyl (PCB 11) is a byproduct of industrial processes and detected in environmental samples. PCB 11 and its metabolites are present in human serum, and emerging evidence demonstrates that PCB 11 is a developmental neurotoxicant. However, little is known about the metabolism of PCB 11 in humans. Here, we investigated the metabolism of PCB 11 and the associated metabolomics changes in HepG2 cells using untargeted high-resolution mass spectrometry. HepG2 cells were exposed for 24 h to PCB 11 in DMSO or DMSO alone. Cell culture media were analyzed with ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry. Thirty different metabolites were formed by HepG2 cells exposed to 10 μM PCB 11, including monohydroxylated, dihydroxylated, methoxylated-hydroxylated, and methoxylated-dihydroxylated metabolites and the corresponding sulfo and glucuronide conjugates. The methoxylated PCB metabolites were observed for the first time in a human-relevant model. 4-OH-PCB 11 (3,3′-dichlorobiphenyl-4-ol) and the corresponding catechol metabolite, 4,5-di-OH-PCB 11 (3′,5-dichloro-3,4-dihydroxybiphenyl), were unambiguously identified based on liquid and gas chromatographic analyses. PCB 11 also altered several metabolic pathways, in particular vitamin B6 metabolism. These results demonstrate that complex PCB 11 metabolite profiles are formed in HepG2 cells that warrant further toxicological investigation, particularly since catechol metabolites are likely reactive and toxic.