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Recently, it was reported that ten cases of bladder cancer occurred among employees, who handled several kinds of aromatic amines, at a Japanese chemical plant. The common aromatic amines were identified as ortho-toluidine, para-toluidine, aniline, ortho-chloroaniline, ortho-anisidine, and 2,4-dimethylaniline. All of these aromatic amines, except ortho-chloroaniline, have been found to be carcinogenic in animals and/or humans. Genotoxic events are known to be crucial steps in the initiation of cancer; information on the genotoxicity of these aromatic amines is insufficient and consistent results have not been obtained. In this study, we examined the genotoxicity of the six different aromatic amines associated with bladder cancer by assessing phosphorylated histone H2AX (γ-H2AX) in a cultured human urothelial cell line, 1T1. We showed that all six aromatic amines generated γ-H2AX. In addition, the γ-H2AX-inducing potential of these six aromatic amines was distinctly different; ortho-chloroaniline and 2,4-dimethylaniline showed particularly high potential, followed by ortho-toluidine, ortho-anisidine, para-toluidine ≒ aniline. The findings of this study may provide important information for the risk assessment of chemicals and for interpreting epidemiological studies on occupational bladder cancer., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Multiple factors, including co-exposure between lifestyle and environmental risks, are important in susceptibility to oxidative DNA damage. However, the underlying mechanism is not fully understood. This study was undertaken to evaluate whether Cytochrome P4501A1 (CYP1A1) methylation can mediate the co-exposure effect between smoking and occupational polycyclic aromatic hydrocarbons (PAH) in development of oxidative DNA damage., Methods: We explored the associations between smoking and occupational PAH co-exposure effect, CYP1A1 methylation and oxidative DNA damage among 500 workers from a coke-oven plant in China. Urine biomarkers of PAH exposure (1-hydroxypyrene, 1-OHP; 2-hydroxynaphthalene, 2-NAP; 2-hydroxyfluorene, 2-FLU; and 9-hydroxyphenanthren, 9-PHE) and a marker of oxidative DNA damage (8-hydroxy- 2'- deoxyguanosine, 8-OHdG) were measured by high performance liquid chromatography. CYP1A1 methylation was measured by pyrosequencing. Finally, mediation analysis was performed to investigate whether CYP1A1 methylation mediated smoking and occupational PAH co-exposure effect on oxidative DNA damage., Results: We observed significant associations of smoking and 1-OHP co-exposure with CYP1A1 hypomethylation (OR: 1.87, 95% CI: 1.01-3.47) and high 8-OHdG (OR: 2.13, 95% CI: 1.14-3.97). There was a significant relationship between CYP1A1 hypomethylation and high 8-OHdG (1st vs. 3rd tertile = 1.58, 95% CI: 1.01-2.47, P for trend = 0.046). In addition, mediation analysis suggested CYP1A1 hypomethylation could explain 13.6% of effect of high 8-OHdG related to smoking and 1-OHP co-exposure., Conclusions: Our findings suggested that the co-exposure effect of smoking and occupational PAH could increase the risk of oxidative DNA damage by a mechanism partly involving CYP1A1 hypomethylation.

Previous publications have indicated that polycyclic aromatic hydrocarbons (PAHs) exposures are associated with increased DNA damage and abnormal cell cycle arrest; however, the details of mechanisms remain largely unknown. This study aimed to quantify the associations of 8-oxoguanine DNA glycosylase (OGG1) methylation with urinary PAHs metabolites, DNA damage and cell cycle arrest, and further to assess the role of OGG1 methylation in mediating the association of urinary PAHs metabolites with DNA damage and cell cycle arrest. Urinary biomarkers of PAHs exposure and a marker of oxidative DNA damage (8-hydroxy-2'-deoxyguanosin, 8-OHdG) were measured by high performance liquid chromatography. Cell cycle of lymphocyte was analysed with flow cytometry and OGG1 methylation in venous blood was measured by pyrosequencing. After adjusting for covariates, urinary 1-OHP levels were positively associated with lymphocyte S phase arrest and oxidative DNA damage, while were negatively associated with G0/G1 phase arrest. OGG1 methylation was not only positively correlated with urinary 1-OHP in a dose-responsive manner (P trend = 0.008) but was also associated with G0/G1 phase arrest (OR: 0.63, 95% CI: 0.41-0.97), S phase arrest (OR: 1.55, 95% CI: 1.01-2.40) and oxidative DNA damage (OR: 1.71, 95% CI: 1.02-2.86). Mediation analysis estimated that OGG1 methylation mediated about 20% of associations between urinary 1-OHP levels and cell cycle arrest and oxidative DNA damage, respectively (all P < 0.05). Our findings suggested that urinary 1-OHP concentrations were associated with cell cycle arrest and oxidative DNA damage by a mechanism partly involving OGG1 methylation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Polycyclic aromatic hydrocarbons (PAH) are well-known to be carcinogenic and the mechanisms that it contributes to oxidative DNA damage and aryl hydrocarbon receptor (AhR)-dependent induction are also well understood. However, little is known about the associations between PAH exposure, AhR expression, and oxidative DNA damage. We investigated their associations of AhR expression and oxidative DNA damage related to PAH exposure among 310 workers from a coke-oven plant in China. Urine biomarkers of PAH exposure (2-hydroxynaphthalene, 2-NAP; 2-hydroxyfluorene, 2-FLU; 9-hydroxyphenanthren, 9-PHE; and 1-hydroxypyrene, 1-OHP) and a marker of oxidative damage (8-hydroxy- 2'- deoxyguanosine, 8-OHdG) were measured by high performance liquid chromatography. AhR expression in venous blood was measured by reverse transcription -polymerase chain reaction. The results showed that increasing levels of urinary 1-OHP was positively associated with high 8-OHdG (OR (95% CI) was 4.01 (1.41-11.45) for 4th quartile, compared with 1st quartile, P for trend = 0.013). The similar associations were also found between urinary 1-OHP and high-AhR expressions (4th vs. 1st quartile = 3.50, 95% CI: 1.24-9.87, P for trend = 0.029). A significant association between AhR expression and high 8-OHdG was also found (4th vs. 1st quartile = 2.44, 95% CI: 1.05-5.70, P for trend = 0.027). In addition, mediation analysis showed the AhR expression could explain 35.9% of the association of oxidative DNA damage related to PAH exposure. Our findings implicated that the association between PAH exposure and oxidative DNA damage may be mediated by AhR expression among Chinese occupational workers., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Benzo [a]pyrene (BaP) have been demonstrated to induce lung cancer risk in humans and many different animal models, with aberrant gene methylation as one of the epigenetic errors; however, the molecular mechanisms remain unclear. Here, we used three types of human lung-derived cells with BaP exposure as a model and attempted to investigate the long non-coding RNA (lncRNA) H19/S-adenosylhomocysteine hydrolase (SAHH) pathway that regulates gene methylation in vitro exposure to BaP. Results showed that compared to the controls, BaP-treated cells H19 expressions were increased in a dose- and time-dependent manner, whereas SAHH protein expressions were decreased. Indeed, H19 binds to and attenuates SAHH expressions and activity, and this interaction will be enhanced by BaP. However, suppression of H19 exaggerates SAHH protein expression and activity exposed to BaP. Although BaP-treated cells H19 single knockdown expectedly increased long interspersed nuclear elements-1 (LINE-1) methylation and inhibited benzo [a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) -DNA adducts formation with altering SAHH protein expressions and activity, the double knockdown restored methylation to the control level and exacerbated BPDE-DNA adducts formation. Overall, our results uncover a H19/SAHH circuit involving gene-methylation alterations by carcinogen BaP., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The mechanisms that long noncoding RNA (lncRNA) H19 binding to S-adenosylhomocysteine hydrolase (SAHH) interacted with DNA methyltransferase 1 (DNMT1) and then regulated DNA damage caused by polycyclic aromatic hydrocarbons (PAHs) remain unclear. A total of 146 occupational workers in a Chinese coke-oven plant in 2014 were included in the final analyses. We used high-performance liquid chromatography mass spectrometry (HPLC–MS) equipped to detect urine biomarkers of PAHs exposure, including 2-hydroxynaphthalene (2-NAP), 2-hydroxyfluorene (2-FLU), 9-hydroxyphenanthrene (9-PHE) and 1-hydroxypyrene (1-OHP). The levels of SAM and SAH in plasma were detected by HPLC-ultraviolet. By constructing various BEAS-2B cell models exposed to 16 μM benzo[a]pyrene (BaP) for 24 h, toxicological parameters reflecting distinct mechanisms were evaluated. We documented that urinary 1-hydroxypyrene (1-OHP) levels were positively associated with blood H19 RNA expression (OR: 1.51, 95% CI: 1.03–2.19), but opposite to plasma SAHH activity (OR: 0.63, 95% CI: 0.41–0.98) in coke oven workers. Moreover, by constructing various BEAS-2B cell models exposed to benzo[a]pyrene (BaP), we investigated that H19 binding to SAHH exaggerated DNMT1 expressions and activity. Suppression of H19 enhanced the interaction of SAHH and DNMT1 in BaP-treated cells, decreased eight-oxoguanine DNA glycosylase 1 (OGG1) methylation, reduced oxidative DNA damage and lessened S phase arrest. However, SAHH or DNMT1 single knockdown and SAHH/DNMT1 double knockdown showed the opposite trend. A H19/SAHH/DNMT1 axis was involved in OGG1 methylation, oxidative DNA damage and cell cycle arrest by carcinogen BaP. [ABSTRACT FROM AUTHOR]

Background: Multiple factors, including co-exposure between lifestyle and environmental risks, are important in susceptibility to oxidative DNA damage. However, the underlying mechanism is not fully understood. This study was undertaken to evaluate whether Cytochrome P4501A1 (CYP1A1) methylation can mediate the co-exposure effect between smoking and occupational polycyclic aromatic hydrocarbons (PAH) in development of oxidative DNA damage.Methods: We explored the associations between smoking and occupational PAH co-exposure effect, CYP1A1 methylation and oxidative DNA damage among 500 workers from a coke-oven plant in China. Urine biomarkers of PAH exposure (1-hydroxypyrene, 1-OHP; 2-hydroxynaphthalene, 2-NAP; 2-hydroxyfluorene, 2-FLU; and 9-hydroxyphenanthren, 9-PHE) and a marker of oxidative DNA damage (8-hydroxy- 2'- deoxyguanosine, 8-OHdG) were measured by high performance liquid chromatography. CYP1A1 methylation was measured by pyrosequencing. Finally, mediation analysis was performed to investigate whether CYP1A1 methylation mediated smoking and occupational PAH co-exposure effect on oxidative DNA damage.Results: We observed significant associations of smoking and 1-OHP co-exposure with CYP1A1 hypomethylation (OR: 1.87, 95% CI: 1.01-3.47) and high 8-OHdG (OR: 2.13, 95% CI: 1.14-3.97). There was a significant relationship between CYP1A1 hypomethylation and high 8-OHdG (1st vs. 3rd tertile = 1.58, 95% CI: 1.01-2.47, P for trend = 0.046). In addition, mediation analysis suggested CYP1A1 hypomethylation could explain 13.6% of effect of high 8-OHdG related to smoking and 1-OHP co-exposure.Conclusions: Our findings suggested that the co-exposure effect of smoking and occupational PAH could increase the risk of oxidative DNA damage by a mechanism partly involving CYP1A1 hypomethylation. [ABSTRACT FROM AUTHOR]