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

• 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
• Journal Title: ENVIRONMENTAL SCIENCE & TECHNOLOGY
• Volume: Volume 54, Number 19
• Publisher: AMER CHEMICAL SOC | 2020-10-06, Pages 12345-12357
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1021/acs.est.0c03476
• Subjects: Health Sciences, Medicine and Surgery; Environmental Sciences
• Keywords: Science & Technology; Technology; Life Sciences & Biomedicine; Engineering, Environmental; Environmental Sciences; Engineering; Environmental Sciences & Ecology; HYDROXYLATED POLYCHLORINATED-BIPHENYLS; SULFATED METABOLITES; IN-VITRO; NON-AROCLOR; 4-CHLOROBIPHENYL PCB3; INHALATION EXPOSURE; HEPATIC-METABOLISM; HUMAN HEPATOCYTES; GREAT-LAKES; HUMAN SERUM

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.