Human Health Effects of Biphenyl: Key Findings and Scientific Issues

Li, Zheng; Hogan, Karen; Cai, Christine; Rieth, Susan

doi:10.1289/ehp.1509730

Cited by 17 publications

(13 citation statements)

References 69 publications

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“…Representing the first group, 2,4-D is a widely used herbicide, suspected to cause mild gastrointestinal irritation and progressive mixed sensorimotor peripheral neuropathy after high-dose skin exposure and congenital malformations; however, the mechanisms of actions are not clear . Belonging to the other group, biphenyl, which is a substance existing in crude oil and coal tar, has been linked to human carcinogenesis, although with unclear mechanisms . Considering that 2,4-D-like and biphenyl-like compounds showed low activity on the targets evaluated by Tox21, we speculated that these two types of compounds have either low biological activity or other potential targets not yet explored.…”

Section: Resultsmentioning

confidence: 99%

Tox21-Based Comparative Analyses for the Identification of Potential Toxic Effects of Environmental Pollutants

Yang

Yin

Zhang

et al. 2022

Environ. Sci. Technol.

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Chemical pollution has become a prominent environmental problem. In recent years, quantitative high-throughput screening (qHTS) assays have been developed for the fast assessment of chemicals' toxic effects. Toxicology in the 21st Century (Tox21) is a well-known and continuously developing qHTS project. Recent reports utilizing Tox21 data have mainly focused on setting up mathematical models for in vivo toxicity predictions, with less attention to intuitive qHTS data visualization. In this study, we attempted to reveal and summarize the toxic effects of environmental pollutants by analyzing and visualizing Tox21 qHTS data. Via PubMed text mining, toxicity/ structure clustering, and manual classification, we detected a total of 158 chemicals of environmental concern (COECs) from the Tox21 library that we classified into 13 COEC groups based on structure and activity similarities. By visualizing these COEC groups' bioactivities, we demonstrated that COECs frequently displayed androgen and progesterone antagonistic effects, xenobiotic receptor agonistic roles, and mitochondrial toxicity. We also revealed many other potential targets of the 13 COEC groups, which were not well illustrated yet, and that current Tox21 assays may not correctly classify known teratogens. In conclusion, we provide a feasible method to intuitively understand qHTS data.

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Section: Resultsmentioning

confidence: 99%

Tox21-Based Comparative Analyses for the Identification of Potential Toxic Effects of Environmental Pollutants

Yang

Yin

Zhang

et al. 2022

Environ. Sci. Technol.

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“…Poplars and other short-rotation trees are excellent targets for remediating POPs ( 9 – 11 ), including PCBs and biphenyl. Biphenyl is an important toxicant itself that continues to be produced extensively ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

A poplar short-chain dehydrogenase reductase plays a potential key role in biphenyl detoxification

Contreras

Merino

Álvarez

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Polychlorinated biphenyls (PCBs) are persistent organic pollutants with severe effects on human health and the biosphere. Plant-based remediation offers many benefits over conventional PCB remediation, but its development has been hampered by our poor understanding of biphenyl metabolism in eukaryotes, among other factors. We report here a major PCB-responsive protein in poplar, a plant model system capable of PCB uptake and translocation. We provide structural and functional evidence that this uncharacterized protein, termed SDR57C, belongs to the heterogeneous short-chain dehydrogenase reductase (SDR) superfamily. Despite sequence divergence, structural modeling hinted at structural and functional similarities between SDR57C and BphB, a central component of the Bph pathway for biphenyl/PCB degradation in aerobic bacteria. By combining gas chromatography/mass spectrometry (GC/MS) profiling with a functional complementation scheme, we found that poplar SDR57C can replace BphB activity in the upper Bph pathway of Pseudomonas furukawaii KF707 and therefore catalyze the oxidation of 2,3-dihydro-2,3-dihydroxybiphenyl (2,3-DHDB) to 2,3-dihydroxybiphenyl (2,3-DHB). Consistent with this biochemical activity, we propose a mechanism of action based on prior quantum studies, general properties of SDR enzymes, and the modeled docking of 2,3-DHDB to the SDR57C-NAD+ complex. The putative detoxifying capacity of SDR57C was substantiated through reverse genetics in Arabidopsis thaliana. Phenotypic characterization of the SDR lines underscored an inducible plant pathway with the potential to catabolize toxic biphenyl derivatives. Partial similarities with aerobic bacterial degradation notwithstanding, real-time messenger RNA quantification indicates the occurrence of plant-specific enzymes and features. Our results may help explain differences in degradative abilities among plant genotypes and also provide elements to improve them.

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“…50 Importantly, the formation of BP metabolites may be associated with adverse effects linked to BP exposure, such as genotoxicity and carcinogenesis. 87 Moreover, PCB 2 biotransformation results in reactive or redox-active intermediates, such as arene oxides, catechols, hydroquinones, and quinones, of PCB 2 and BP. 21,74,88 Both arene oxides and quinones can readily react with cellular nucleophiles, including proteins and DNA.…”

Section: Comparison Of Pcb 2 and Pcb 11mentioning

confidence: 99%

Metabolism of 3-Chlorobiphenyl (PCB 2) in a Human-Relevant Cell Line: Evidence of Dechlorinated Metabolites

Zhang

Flor

et al. 2022

Environ. Sci. Technol.

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Lower chlorinated polychlorinated biphenyls (LC-PCBs) and their metabolites make up a class of environmental pollutants implicated in a range of adverse outcomes in humans; however, the metabolism of LC-PCBs in human models has received little attention. Here we characterize the metabolism of PCB 2 (3-chlorobiphenyl), an environmentally relevant LC-PCB congener, in HepG2 cells with in silico prediction and nontarget high-resolution mass spectrometry. Twenty PCB 2 metabolites belonging to 13 metabolite classes, including five dechlorinated metabolite classes, were identified in the cell culture media from HepG2 cells exposed for 24 h to 10 μM or 3.6 nM PCB 2. The PCB 2 metabolite profiles differed from the monochlorinated metabolite profiles identified in samples from an earlier study with PCB 11 (3,3′-dichlorobiphenyl) under identical experimental conditions. A dechlorinated dihydroxylated metabolite was also detected in human liver microsomal incubations with monohydroxylated PCB 2 metabolites but not PCB 2. These findings demonstrate that the metabolism of LC-PCBs in human-relevant models involves the formation of dechlorination products. In addition, untargeted metabolomic analyses revealed an altered bile acid biosynthesis in HepG2 cells. Our results indicate the need to study the disposition and toxicity of complex PCB 2 metabolites, including novel dechlorinated metabolites, in human-relevant models.

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Human Health Effects of Biphenyl: Key Findings and Scientific Issues

Cited by 17 publications

References 69 publications

Tox21-Based Comparative Analyses for the Identification of Potential Toxic Effects of Environmental Pollutants

Tox21-Based Comparative Analyses for the Identification of Potential Toxic Effects of Environmental Pollutants

A poplar short-chain dehydrogenase reductase plays a potential key role in biphenyl detoxification

Metabolism of 3-Chlorobiphenyl (PCB 2) in a Human-Relevant Cell Line: Evidence of Dechlorinated Metabolites

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