Effects of H19/SAHH/DNMT1 on the Oxidative DNA Damage Related to Benzo[a]Pyrene Exposure

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 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), 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 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.

Dose–response relationships between polycyclic aromatic hydrocarbon exposure and blood cell counts among coke oven workers: a sex-stratified analysis

ObjectivesTo explore sex differences and dose–response relationships between nine urinary polycyclic aromatic hydrocarbon (PAH) metabolites and neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR) and complete blood counts among coke oven workers.Design and settingA cross-sectional study with stratified sex was conducted in Shanxi, China.ParticipantsA total of 458 male workers and 226 female workers were selected.Primary and secondary outcome measuresGeneral linear models, p values for trend tests and natural cubic spline models were used to explore the dose–response relationships between nine urinary PAH metabolites and NLR, PLR and complete blood counts.ResultCompared with male workers, female workers had lower exposure level of PAH (0.95 ng/mL vs 1.38 ng/mL). Only among female workers did we observe that a 1-unit increase in lg(1-OHPyr) was related to a 0.149 (95% CI: 0.055 to 0.242; p for trend=0.041) and 0.103 (95% CI: 0.025 to 0.181; p for trend=0.007) increase in lg(NLR) and lg(PLR), and a 0.116 (95% CI: −0.179 to –0.054; p for trend=0.007) decrease in lg(lymphocyte counts (LYMs)). A 1-unit increase in lg(2-OHNap) was related to a 0.045 (95% CI: 0.003 to 0.086; p for trend=0.037) increase in lg(PLR) and a 0.029 (95% CI: −0.056 to –0.002; p for trend=0.030) and 0.016 (95% CI: −0.029 to –0.003; p for trend=0.010) decrease in lg(white blood cell counts (WBCs)) and lg(haemoglobin (HGB)).ConclusionFemale workers’ NLR, PLR, WBCs, HGB and LYMs may be more susceptible than those of male workers when affected by PAH.

Joint Effects of Co-Exposure to Polycyclic Aromatic Hydrocarbons Exposure and Smoking with XPC Polymorphisms on Damage in Exon 2 of KRAS Gene Among Young Coke-Oven Workers

Background Genetic polymorphisms may contribute to variable individual susceptibility to DNA damage induced by co-exposure to polycyclic aromatic hydrocarbons (PAHs) and smoking. Here, we evaluate the joint effects of co-exposure to PAHs and smoking with polymorphisms in XPC, alone or combined, on damage in exons. Methods 288 healthy male coke-oven workers were enrolled into this study, urinary 1-hydroxypyrene (1-OH-pyr), as an indirect and sensitive indicator of PAHs exposure, was detected. Base modification in exons of KRAS and BRAF gene, and polymorphisms of XPC were determined by real-time PCR in plasma samples. Results We observed urinary 1-OH-pyr was positively related to damage index of exon 2 of KRAS gene (KRAS-2) and damage index of exon 15 of BRAF gene (BRAF-15) (both p < 0.001), and KRAS-2 and BRAF-15 were both significantly associated with increased urinary 1-OH-pyr (both p trend < 0.001). A stratified analysis found that urinary 1-OH-pyr was found to be significantly associated with KRAS-2 in both smokers (p < 0.001) and nonsmokers (p < 0.05), while urinary 1-OH-pyr was significantly associated with BRAF-15 only in smokers (p < 0.001). Additionally, rs2228001 in the XPC gene was positively associated with KRAS-2 (p trend < 0.001), and the high levels of 1-OH-pyr were linearly associated with KRAS-2 only in rs2228001 GG+GT genotype carriers (p < 0.001); However, another SNP rs3731055 in the XPC gene was associated with lower KRAS-2 (p trend = 0.006), and the high levels of 1-OH-pyr were linearly associated with KRAS-2 only in rs3731055 GG genotype carriers (p < 0.001). Moreover, KRAS-2 significantly increased with high levels of 1-OH-pyr exposure, smoking, rs2228001 G-allele, and rs3731055 GG homozygote genotype, and we found the most severe KRAS-2 among subjects carrying all 4 of the above risk factors. Conclusions Our findings indicated that the co-exposure effect of PAHs and cigarette smoking could increase the risk of damage in exon 2 of KRAS by a mechanism partly involving XPC polymorphisms.

Dose–response relationship between urinary PAH metabolites and blood viscosity among coke oven workers: a cross-sectional study

ObjectivesPolycyclic aromatic hydrocarbons (PAHs) have been proven to be a risk factor for cardiovascular disease in coke oven workers, and increased plasma viscosity is a signal for higher risk of catching up cardiovascular disease. We want to explore whether the plasma viscosity is affected by the concentration of PAHs.DesignOur study is a cross-sectional dose–response study.SettingParticipants in this study came from a coke plant in Taiyuan, Shanxi.ParticipantsWe used data of 693 coke oven workers in Taiyuan.Primary and secondary outcome measuresWe assumed that plasma viscosity would increase as the concentration of PAHs metabolites in urine increases. We found that 2-hydroxyfluorene (OHFLU2) and plasma viscosity have a stable linear relationship in different statistical methods.ResultsWe found that plasma viscosity increased by 1.14 (mPa.s,30/s) for each ng/mL of 2-OHFLU urinary (correlation coefficient range: 0.54–1.74, p<0.05).ConclusionsThe results of this study could provide evidence for coke oven workers to prevent cardiovascular disease by checking whether plasma viscosity is elevated.

Effects of H19/SAHH/DNMT1 on the oxidative DNA damage related to Benzo[a]pyrene exposure

Background: 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 PAHs remain unclear. Results: 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 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. Conclusions: A H19/SAHH/DNMT1 axis was involved in OGG1 methylation, oxidative DNA damage and cell cycle arrest by carcinogen BaP.

Mixture Analysis of Associations between Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Sperm Oxidative DNA Damage

Objective This study aimed to determine (i) associations between levels of the polycyclic aromatic hydrocarbon (PAH) mixture with 16 targeted PAH compounds in the personal breathing zone area and sperm oxidative DNA damage, (ii) associations between levels of individual PAH compounds and sperm oxidative DNA damage, (iii) oxidative stress as the mode of action for the genotoxic effects on sperm, and (iv) any dose–response relationship between exposure to the PAH mixture and/or individual PAH compounds and sperm oxidative DNA damage. Methods Sixteen targeted PAH compounds in the personal breathing zone area of 38 coke-oven workers and 24 control subjects were quantified using gas chromatography–mass spectrometry. Sperm oxidative damage and status were evaluated by measuring levels of sperm 7,8-dihydro-8-oxoguanie (8-oxodGuo), seminal malondialdehyde (MDA) and seminal reactive oxygen species (ROS). Bayesian kernel machine regression with hierarchical variable selection process was employed to determine associations of the PAH mixture and the biomarkers of sperm oxidative damage. A novel grouping approach needed for the hierarchical variable selection process was developed based on PAH bay region and molecular weight. Results The PAH mixture exhibited a positive trend with increased sperm 8-oxodGuo levels at their lower percentiles (25th–50th). The exposure of the PAH mixture was associated with increased MDA levels in sperm. Bay and bay-like regions of the PAH mixture were the most important group for estimating the associations between the PAH mixture and sperm oxidative stress status. Benzo[a]anthracene was the main individual PAH compound that was associated with increased MDA levels. Conclusion Sperm oxidative DNA damage induced by occupational exposure to the PAH mixture had a suggestive association with increased MDA levels in coke-oven workers. Finally, the study identified that the individual PAH compound, benzo[a]anthracene, was the primary driver for the suggestive association between the PAH mixture and sperm oxidative damage.