Urine Excretion, Organ Distribution, and Placental Transfer of 6PPD and 6PPD-Quinone in Mice and Potential Developmental Toxicity through Nuclear Receptor Pathways

Zhao, Haoqi Nina; Thomas, Sydney P.; Zylka, Mark J.; Dorrestein, Pieter C.; Hu, Wenxin

doi:10.1021/acs.est.3c05026

Cited by 34 publications

(3 citation statements)

References 79 publications

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“…The calculated BCF values revealed the preferential accumulation in organs following the order of intestine > brain > eye > muscle > heart > liver (Table S7). After intraperitoneal injection or oral ingestion, 6PPDQ concentrations were notably higher in the liver compared to the brain in mice, − suggesting that the liver, rather than the brain, may be the major target organ for 6PPDQ in this species. Interestingly, the accumulation profile of 6PPDQ in zebrafish tissues observed in our study differed from that observed in mice tissues.…”

Section: Discussionmentioning

confidence: 99%

Tissue Accumulation and Biotransformation of 6PPD-Quinone in Adult Zebrafish and Its Effects on the Intestinal Microbial Community

Liao,

Chen,

Liu

et al. 2024

Environ. Sci. Technol.

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The pronounced lethality of N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPD-quinone or 6PPDQ) toward specific salmonids, while sparing other fish species, has received considerable attention. However, the underlying cause of this species-specific toxicity remains unresolved. This study explored 6PPDQ toxicokinetics and intestinal microbiota composition in adult zebrafish during a 14-day exposure to environmentally realistic concentrations, followed by a 7-day recovery phase. Predominant accumulation occurred in the brain, intestine, and eyes, with the lowest levels in the liver. Six metabolites were found to undergo hydroxylation, with two additionally undergoing O-sulfonation. Semiquantitative analyses revealed that the predominant metabolite featured a hydroxy group situated on the phenyl ring adjacent to the quinone. This was further validated by assessing enzyme activity and determining in silico binding interactions. Notably, the binding affinity between 6PPDQ and zebrafish phase I and II enzymes exceeded that with the corresponding coho salmon enzymes by 1.04−1.53 times, suggesting a higher potential for 6PPDQ detoxification in tolerant species. Whole-genome sequencing revealed significant increases in the genera Nocardioides and Rhodococcus after exposure to 6PPDQ. Functional annotation and pathway enrichment analyses predicted that these two genera would be responsible for the biodegradation and metabolism of xenobiotics. These findings offer crucial data for comprehending 6PPDQ-induced species-specific toxicity.

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Section: Discussionmentioning

confidence: 99%

Tissue Accumulation and Biotransformation of 6PPD-Quinone in Adult Zebrafish and Its Effects on the Intestinal Microbial Community

Liao,

Chen,

Liu

et al. 2024

Environ. Sci. Technol.

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“…This result is consistent with that found in juvenile coho salmon, that 6PPD-Q exhibited high toxicity while 6PPD did not [ 1 ]. Zhao et al treated mice with 6PPD and 6PPD-Q, finding that 6PPD-Q showed ~1.5–8-times higher bioaccumulation than 6PPD in all tissue types, and the liver appeared to be the major target organ for both 6PPD and 6PPD-Q after oral ingestion [ 13 ]. Di et al found that 6PPD-Q was more stable in water solutions than 6PPD, indicating that the toxic effects of 6PPD-Q on sensitive species could be persistent in water [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of 6PPD-Quinone on Human Liver Cell Lines as Revealed with Cell Viability Assay and Metabolomics Analysis

Qi,

Qiu,

Wei

et al. 2024

Toxics

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N-(1,3-Dimethyl butyl)-N′-phenyl-phenylenediamine-quinone (6PPD-Q) is a derivative of the widely used rubber tire antioxidant 6PPD, which was first found to be acutely toxic to coho salmon. Subsequent studies showed that 6PPD-Q had species-specific acute toxicity in fishes and potential hepatotoxicity in mice. In addition, 6PPD-Q has been reported in human urine, demonstrating the potential widespread exposure of humans to this chemical. However, whether 6PPD-Q poses a higher risk to humans than its parent compound, 6PPD, and could cause adverse effects in humans is still unclear. In this study, we utilized two human liver cell models (the human proto-hepatocyte model L02 and the human hepatocellular carcinoma cell line HepG2) to investigate the potentially differential effects of these two chemicals. Cell viability curve analysis showed that 6PPD-Q had lower IC50 values than 6PPD for both liver cell lines, suggesting higher toxicity of 6PPD-Q to human liver cells than 6PPD. In addition, L02 cells are more sensitive to 6PPD-Q exposure, which might be derived from its weaker metabolic transformation of 6PPD-Q, since significantly lower levels of phase I and phase II metabolites were detected in 6PPD-Q-exposed L02 cell culture medium. Furthermore, pathway analysis showed that 6PPD-Q exposure induced changes in phenylalanine, tyrosine, and tryptophan biosynthesis and tyrosine metabolism pathways in L02 cells, which might be the mechanism underlying its liver cell toxicity. Gene expression analysis revealed that exposure to 6PPD-Q induced excessive ROS production in L02 cells. Our results further supported the higher risk of 6PPD-Q than 6PPD and provided insights for understanding the effects of 6PPD-Q on human health.

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“…AAs are generally subdivided into p -phenylenediamines (PPDs), diphenylamines (DPAs), and naphthylamines (NPAs) . Recently, a ubiquitous quinone derivative of the tire rubber antioxidant N -(1,3-dimethylbutyl)- N ′-phenyl-PPD (6PPD), called 6PPD-quinone (6PPD-Q), has been identified as the crucial toxicant responsible for acute mortality in Coho salmon, making PPDs and PPD-derived quinones (PPD-Qs) attract worldwide attention. − Under this background, other AAs, including DPAs and NPAs, have been also brought into the purview of environmental research by our group and other groups. ,, To date, AAs, especially PPDs, have been widely detected in various environmental media and biota. ,− Although toxicological information on AAs remains quite limited, available studies have shown that DPAs possess high bioaccumulation potentials and can induce damage to the liver, spleen, and kidney of mammals. − Additionally, PPDs and NPAs can pose risks to aquatic organisms − and hepatotoxicity and developmental toxicity to mammals. , Currently, human exposure to AAs remains under-researched. Only a few recent studies confirmed the presence of 6PPD and/or 6PPD-Q in human urine, serum, and cerebrospinal fluid. − Given their environmentally widespread occurrence and toxic effects, human biomonitoring of AAs is urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Occurrence of Multiple Classes of Emerging Synthetic Antioxidants, Including p-Phenylenediamines, Diphenylamines, Naphthylamines, Macromolecular Hindered Phenols, and Organophosphites, in Human Milk: Implications for Infant Exposure

Liang,

Ge,

Deng

et al. 2024

Environ. Sci. Technol. Lett.

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Synthetic antioxidants (AOs) have received increasing attention in recent years due to their environmental ubiquity. However, lactational exposure to these emerging contaminants of current concern remains unknown. In this study, 21 amine antioxidants, 18 macromolecular hindered phenol antioxidants, 3 organophosphite antioxidants, and 2 p-phenylenediamine-derived quinones (PPD-Qs) were integrated into a dedicated screening in human milk from South China. Among all 42 target AOs, 19 were detected, but no PPD-Qs were detected in any of the samples. Eight AOs, including N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD), were frequently detected in more than half of the samples. The summed concentrations of all detectable AOs in human milk ranged from 133 to 7,560 pg/mL, with a median of 713 pg/mL. Significant correlations were observed among the concentrations of amine and phenol antioxidants. The preliminary risk assessment revealed that under the high exposure scenario, the overall daily intake of all identified AOs through breastfeeding might pose a non-negligible health risk to newborns. This study is the first to attempt to comprehensively identify a wide range of emerging AOs prevalent in human milk. The findings call for urgent concern for infant exposure to these widely used but less well evaluated chemicals and a possible increased accumulative risk in the future.

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Urine Excretion, Organ Distribution, and Placental Transfer of 6PPD and 6PPD-Quinone in Mice and Potential Developmental Toxicity through Nuclear Receptor Pathways

Cited by 34 publications

References 79 publications

Tissue Accumulation and Biotransformation of 6PPD-Quinone in Adult Zebrafish and Its Effects on the Intestinal Microbial Community

Tissue Accumulation and Biotransformation of 6PPD-Quinone in Adult Zebrafish and Its Effects on the Intestinal Microbial Community

Effects of 6PPD-Quinone on Human Liver Cell Lines as Revealed with Cell Viability Assay and Metabolomics Analysis

Occurrence of Multiple Classes of Emerging Synthetic Antioxidants, Including p-Phenylenediamines, Diphenylamines, Naphthylamines, Macromolecular Hindered Phenols, and Organophosphites, in Human Milk: Implications for Infant Exposure

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