Oxidative stress and genotoxicity in 1,4-dioxane liver toxicity as evidenced in a mouse model of glutathione deficiency

Chen, Ying; Wang, Yewei; Charkoftaki, Georgia; Orlicky, David J.; Davidson, Emily A.; Wan, Fengjie; Ginsberg, Gary; Thompson, David C.; Vasiliou, Vasilis

doi:10.1016/j.scitotenv.2021.150703

Cited by 15 publications

(5 citation statements)

References 40 publications

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“…64 Otherwise, malondialdehyde (MDA) and 4-HNE are formed as the main products of lipid peroxidation, which can be used as a sensitive diagnostic marker of oxidative damage. 65,66 In this study, exposure to 6:6 and 8:8 PFPiAs stimulated the formation of SOD and GSH while suppressing the expression of GPx in both male and female carp (Figure S10A which corresponded to the accumulated level of ROS (Figure S10(D,E)). Although the lack of antibody specificity resulted in widespread positive staining of 4-HNE, parallel negative control confirmed the widespread brown staining to be indicative of anti-4-HNE positive expression (Figure S6B).…”

Section: ■ Results and Discussionmentioning

confidence: 54%

“…In addition, GSH, serving as an important antioxidant, can combine with peroxides and free radicals to protect vital organs from the damage of free radicals . Otherwise, malondialdehyde (MDA) and 4-HNE are formed as the main products of lipid peroxidation, which can be used as a sensitive diagnostic marker of oxidative damage. , In this study, exposure to 6:6 and 8:8 PFPiAs stimulated the formation of SOD and GSH while suppressing the expression of GPx in both male and female carp (Figure S10A–C). The results here imply that 6:6 and 8:8 PFPiAs promoted the generation of ROS but inhibited its decomposition.…”

Section: Resultsmentioning

confidence: 62%

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Underlying Mechanisms for the Sex- and Chemical-Specific Hepatotoxicity of Perfluoroalkyl Phosphinic Acids in Common Carp (Cyprinus carpio)

Liu,

Yi,

et al. 2023

Environ. Sci. Technol.

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The hepatotoxicities of perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been extensively investigated, while little is known about the sex-specific differences. In this study, common carp were exposed to the emerging perfluoroalkyl phosphinic acids (6:6 and 8:8 PFPiAs) for 14 days to disclose sex-specific hepatotoxicity. Apparent hepatotoxicity, including cell necrosis, apoptosis, and steatosis, was observed in both male and female carp liver. The observed hepatocyte steatosis was predominantly attributed to the dysregulation of hepatic lipid metabolism but was based on sex-specific mechanisms. It was manifested as inhibited oxidative decomposition of fatty acids (FAs) in the female liver, whereas it enhanced the uptake of FAs into the male liver, both of which led to excessive lipid accumulation. Untargeted lipidomics validated that the metabolism pathways of FA, sphingolipid, glycerolipid, and glycerophospholipid were disrupted by both compounds, leading to the generation of reactive oxygen species and oxidative stress. The oxidative stress further evolved into inflammation, manifested as promoted expression of proinflammatory cytokines and repressed expression of anti-inflammatory cytokines. Consistently, all of the changes were more noticeable in male carp, suggesting that male fish were more susceptible to PFPiA disruption. 8:8 PFPiA was less accumulated but caused stronger hepatotoxicity than 6:6 PFPiA, possibly because of the stronger binding capacity of 8:8 PFPiA to nuclear transcription factors mediating lipid metabolism and inflammation. The findings of this study highlight the significance of sex-and chemical-dependent bioaccumulation and the toxicity of PFASs in organisms.

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Section: ■ Results and Discussionmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 62%

Underlying Mechanisms for the Sex- and Chemical-Specific Hepatotoxicity of Perfluoroalkyl Phosphinic Acids in Common Carp (Cyprinus carpio)

Liu,

Yi,

et al. 2023

Environ. Sci. Technol.

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“…Alcohol abuse is a prototypical situation associated with CYP2E1 induction and CYP2E1-generated ROS but there is increasing evidence that other xenobiotics can also enhance CYP2E1 expression and activity in liver or other tissues. For instance, this has been shown for the industrial toxicants vinyl chloride and 1,4-dioxane [ 80 , 81 ] and for different pesticides including methoxychlor, phoxim, atrazine, maneb and paraquat [ 82 , 83 , 84 , 85 , 86 ]. A recent study also reported hepatic CYP2E1 induction in rats treated with the endocrine disruptor bisphenol A [ 87 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Role of Mitochondrial Cytochrome P450 2E1 in Healthy and Diseased Liver

Massart

Begriche

Hartman

et al. 2022

Cells

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Cytochrome P450 2E1 (CYP2E1) is pivotal in hepatotoxicity induced by alcohol abuse and different xenobiotics. In this setting, CYP2E1 generates reactive metabolites inducing oxidative stress, mitochondrial dysfunction and cell death. In addition, this enzyme appears to play a role in the progression of obesity-related fatty liver to nonalcoholic steatohepatitis. Indeed, increased CYP2E1 activity in nonalcoholic fatty liver disease (NAFLD) is deemed to induce reactive oxygen species overproduction, which in turn triggers oxidative stress, necroinflammation and fibrosis. In 1997, Avadhani’s group reported for the first time the presence of CYP2E1 in rat liver mitochondria, and subsequent investigations by other groups confirmed that mitochondrial CYP2E1 (mtCYP2E1) could be found in different experimental models. In this review, we first recall the main features of CYP2E1 including its role in the biotransformation of endogenous and exogenous molecules, the regulation of its expression and activity and its involvement in different liver diseases. Then, we present the current knowledge on the physiological role of mtCYP2E1, its contribution to xenobiotic biotransformation as well as the mechanism and regulation of CYP2E1 targeting to mitochondria. Finally, we discuss experimental investigations suggesting that mtCYP2E1 could have a role in alcohol-associated liver disease, xenobiotic-induced hepatotoxicity and NAFLD.

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“…Such effects are threshold-dependent. Oxidative damage might also play a role [ 838 ]. Tumors of nasal passages were attributed to inhalation of drinking water containing 1,4-dioxane [ 815 , 839 ].…”

Section: Epigenetic Carcinogens or Carcinogens With Uncertain Mode Of...mentioning

confidence: 99%

Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk

Kobets

Smith

Williams

2022

Foods

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Commonly consumed foods and beverages can contain chemicals with reported carcinogenic activity in rodent models. Moreover, exposures to some of these substances have been associated with increased cancer risks in humans. Food-borne carcinogens span a range of chemical classes and can arise from natural or anthropogenic sources, as well as form endogenously. Important considerations include the mechanism(s) of action (MoA), their relevance to human biology, and the level of exposure in diet. The MoAs of carcinogens have been classified as either DNA-reactive (genotoxic), involving covalent reaction with nuclear DNA, or epigenetic, involving molecular and cellular effects other than DNA reactivity. Carcinogens are generally present in food at low levels, resulting in low daily intakes, although there are some exceptions. Carcinogens of the DNA-reactive type produce effects at lower dosages than epigenetic carcinogens. Several food-related DNA-reactive carcinogens, including aflatoxins, aristolochic acid, benzene, benzo[a]pyrene and ethylene oxide, are recognized by the International Agency for Research on Cancer (IARC) as causes of human cancer. Of the epigenetic type, the only carcinogen considered to be associated with increased cancer in humans, although not from low-level food exposure, is dioxin (TCDD). Thus, DNA-reactive carcinogens in food represent a much greater risk than epigenetic carcinogens.

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Oxidative stress and genotoxicity in 1,4-dioxane liver toxicity as evidenced in a mouse model of glutathione deficiency

Cited by 15 publications

References 40 publications

Underlying Mechanisms for the Sex- and Chemical-Specific Hepatotoxicity of Perfluoroalkyl Phosphinic Acids in Common Carp (Cyprinus carpio)

Underlying Mechanisms for the Sex- and Chemical-Specific Hepatotoxicity of Perfluoroalkyl Phosphinic Acids in Common Carp (Cyprinus carpio)

Role of Mitochondrial Cytochrome P450 2E1 in Healthy and Diseased Liver

Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk

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