Comparison of sensitivity between blood parameters and a genotoxic biomarker at low blood Pb levels: A population-based study.

BACKGROUND: Previous studies reported that lead (Pb) exposure induced adverse health effects at high exposure concentrations, however, there have been limited data on sensitivity comparisons among different health outcomes at low blood Pb levels. OBJECTIVES: To compare sensitivity between blood parameters and a genotoxic biomarker among workers exposed to low blood Pb levels (< 20 µg/dl), and to estimate a benchmark dose (BMD). METHODS: Pb-exposed workers were recruited from a lead-acid storage battery plant. Their blood lead levels (BLLs) were measured. Blood parameters and micronuclei (MN) frequencies were determined. Multivariate linear or Poisson regression was used to analyze relationships between blood parameters or MN frequencies with BLLs. Two BMD software were used to calculate BMD and its 95 % lower confidence limit (BMDL) for BLLs. RESULTS: The median BLL for 611 workers was 10.44 µg/dl with the 25th and 75th percentile being 7.37 and 14.62 µg/dl among all participants. There were significantly negative correlations between blood parameters and BLLs. However, MN frequencies correlated positively with BLLs (all P<0.05). Results from the two BMD software revealed that the dichotomous model was superior to the continuous model, and the BMDL for BLL derived from red blood cell (RBC) was 15.11 µg/dl, from hemoglobin (HGB) was 8.50 µg/dl, from mean corpuscular hemoglobin (MCH) was 7.87 µg/dl, from mean corpuscular hemoglobin concentration (MCHC) was 3.98 µg/dl, from mean corpuscular volume (MCV) was 11.44 µg/dl, and from hematocrit (HCT) was 6.65 µg/dl. The conservative BMDL obtained from the MN data was 7.52 µg/dl. CONCLUSION: Our study shows that low dose Pb exposure caused decrease of blood parameters and increase of MN frequencies. The genotoxic biomarker was more sensitive than most blood parameters. BMDLs for BLL derived from MN frequencies and the red blood cell indicators should be considered as new occupational exposure limits. Our results suggest that MN assay can be considered as a part of occupational health examination items.

The Relationships Between Blood Pb Levels and Blood Pressure Among Lead-Exposed Workers in China: A Repeated-Measure Study.

OBJECTIVES: To explore the differences in the increase of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in 3 consecutive years among lead (Pb) workers. METHODS: Four hundred forty-eight Pb workers were enrolled in this repeated-measure study. Blood Pb, SBP, and DBP were measured in 2015 to 2017. Repeated measure of analysis of variance was used to compare the differences in the increase of SBP and DBP. RESULTS: The mean SBP values were 124.0/125.5/126.9 mm Hg, and the mean DBP values were 75.4/77.4/77.8 mm Hg from 2015 to 2017. The differences in the increase of SBP and DBP were 2.94/2.42 mm Hg during the 3-year period. The average annual increase of SBP or DBP showed an upward trend in different Pb dose groups ( F = 4.904, P = 0.002; F = 3.612, P = 0.013). CONCLUSIONS: Lead exposure caused average annual increases in SBP and DBP with 0.98 and 0.81 mm Hg, which provided basic data for health surveillance.

Associations between DNA methylation and genotoxicity among lead-exposed workers in China.

Studies have shown that lead (Pb) exposure caused genotoxicity, however, the underlying mechanisms remain unclear. A mechanism may be via DNA methylation which is one of the most widely studied epigenetic regulations for cellular activities. Whether this is involved in Pb-induced genotoxicity has rarely been studied. Our study aimed to examine whether DNA methylation was associated with Pb exposure and genotoxicity, and to explore its potential mediating roles. A total of 250 Pb-exposed workers were enrolled. Blood lead levels (BLLs) and genotoxic biomarkers (Micronuclei and Comet) were analyzed. Methylation levels at CpG sites of LINE1 and Alu and promoter region of P53, BRCA1, TRIM36 and OGG1 were measured by pyrosequencing. Generalized linear model (GLM) combined with restricted cubic splines (RCS) were used to analyze relationships between Pb exposure, DNA methylation and genotoxicity. Mediation effect was used to explore mediating roles of DNA methylation. The distribution of BLLs was right-skewed and showed wide ranges from 23.7 to 636.2 µg/L with median (P25, P75) being 218.4 (106.1, 313.9) µg/L among all workers. Micronuclei frequencies showed Poisson distribution [1.94 ± 1.88‰] and Comet tail intensity showed normal distribution [1.69 ± 0.93%]. GLM combined with RCS showed that Alu methylation was negatively associated with BLLs, while P53 and OGG1 methylation were positively associated with BLLs. Micronuclei were negatively associated with Alu and TRIM36 methylation but positively with P53 methylation. Comet was positively associated with P53 and BRCA1 methylation. Mediation effect showed that Alu methylation mediated 7% effects on association between Pb exposure and micronuclei, whereas, P53 methylation mediated 14% and BRCA1 mediated 9% effects on association between Pb exposure and Comet. Our data show that Pb exposure induced changes of global and gene-specific DNA methylation which mediated Pb-induced genotoxicity.

Occupational lead exposure on genome-wide DNA methylation and DNA damage.

Lead (Pb) exposure can induce DNA damage and alter DNA methylation but their inter-relationships have not been adequately determined. Our overall aims were to explore such relationships and to evaluate underlying epigenetic mechanisms of Pb-induced genotoxicity in Chinese workers. Blood Pb levels (BLLs) were determined and used as individual's Pb-exposure dose and the Comet assay (i.e., % tail DNA) was conducted to evaluate DNA damage. In the screening assay, 850 K BeadChip sequencing was performed on peripheral blood from 10 controls (BLLs ≤100 µg/L) and 20 exposed workers (i.e., 10 DNA-damaged and 10 DNA-undamaged workers). Using the technique, differentially methylated positions (DMPs) between the controls and the exposed workers were identified. In addition, DMPs were identified between the DNA-undamaged and DNA-damaged workers (% tail DNA >2.14%). In our validation assay, methylation levels of four candidate genes were measured by pyrosequencing in an independent sample set (n = 305), including RRAGC (Ras related GTP binding C), USP1 (Ubiquitin specific protease 1), COPS7B (COP9 signalosome subunit 7 B) and CHEK1 (Checkpoint kinase 1). The result of comparisons between the controls and the Pb-exposed workers show that DMPs were significantly enriched in genes related to nerve conduction and cell cycle. Between DNA-damaged group and DNA-undamaged group, differentially methylated genes were enriched in the pathways related to cell cycle and DNA integrity checkpoints. Additionally, methylation levels of RRAGC and USP1 were negatively associated with BLLs (P < 0.05), and the former mediated 19.40% of the effect of Pb on the % tail DNA. These findings collectively indicated that Pb-induced DNA damage was closely related to methylation of genes in cell cycle regulation, and methylation levels of RRAGC were involved in Pb-induced genotoxicity.

Global and gene-specific promoter methylation, and micronuclei induction in lead-exposed workers: A cross-sectional study.

Perturbation of epigenetic regulation is a well-established mechanism for cancer but its role for lead (Pb)-associated toxicity has not been adequately investigated. We aimed to investigate whether occupational Pb exposure is associated with micronuclei (MN) frequency and to further explored the mediating roles of epigenetic gene regulation. All the Pb-exposed workers recruited from a Chinese acid battery factory, blood lead levels (BLLs) and MN frequency in lymphocytes were measured. In addition, methylation levels of seven genes (Line-1, RASSF1A, RUNX3, p16, CYP26C1, hMLH1, p15) were examined among 230 workers. Robust Poisson regression model was used to investigate the association between BLLs and MN frequency. Mediation analysis was used to explore the mediating role of specific DNA methylation. Among total 677 participants, 71% were male, median BLLs was 229.1 µg/L (P25  = 155.5, P75  = 319.3; ranged from 8.9 to 647.7 µg/L), mean MN frequency was 2.5‰ (SD = 1.8‰; ranged from 0 to 9‰). Results from base model, adjusted for age, sex, and body mass index, showed that MN frequency would increase 1.38 (95%confidential interval: 1.34, 1.43) per 100 µg/L increment in BLLs. Using categorized exposure variable analyses, a BLLs dose-response increase in MN frequency was observed: 2.74 (2.13, 3.51), 3.43 (2.73, 4.32), 4.41 (3.89, 5.01) to 6.86 (6.02, 7.81). Mediation analysis indicated that Line-1 methylation significantly mediated 3.6% of the association of BLLs with MN frequency. Occupational Pb exposure induces MN frequency in a dose-response relationship. Part of this association was mediated by Line-1 promotor methylation.

Plasma cholinesterase activity is influenced by interactive effect between omethoate exposure and CYP2E1 polymorphisms.

The aim of this study was to explore the association between metabolizing enzyme gene polymorphisms and the decrease in cholinesterase activity induced by omethoate exposure. A total of 180 workers exposed to omethoate over an extended period were recruited along with 115 healthy controls. Cholinesterase activity in whole blood, erythrocyte, and plasma was detected using acetylthiocholine and the dithio-bis-(nitrobenzoic acid) method. Six polymorphic loci of GSTT1(+/-), GSTM1(+/-), GSTP1 rs1695, CYP2E1 rs6413432, CYP2E1 rs3813867, and PON2 rs12026 were detected by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The gene-environment interactions were analyzed using the generalized linear model method. The cholinesterase activity of erythrocyte and plasma in the exposure group was significantly lower than that in the control group (P < 0.001) in general. The plasma cholinesterase activity in the TT + AT genotype in CYP2E1 rs6413432 was lower than that in the AA genotype in the exposure group (P = 0.016). Interaction between the AA genotype in CYP2E1 rs6413432 and omethoate exposure had a significant effect on plasma cholinesterase activity (P = 0.079). The decrease in plasma cholinesterase activity was associated with interaction between the AA genotypes in rs6413432 and omethoate exposure.

Early occupational exposure to lead on neutrophil-to-lymphocyte ratio and genotoxicity.

BACKGROUND: Lead (Pb) is known to induce detrimental health effects in exposed populations, including hematotoxicity and genotoxicity. Complete blood count (CBC) is a cost-effective and easy way to determine toxicity, and variations in proportion of different types of leukocytes: neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) are further evidence of hematotoxicity. However, few studies have been conducted to systematically evaluate effects of occupational Pb exposure on NLR and LMR, and their associations with genotoxicity. OBJECTIVES: Our study was aimed to systematically assess the effects of current occupational Pb exposure on NLR and LMR, and their associations with genotoxicity. METHODS: Our investigation was performed on 1176 workers from a newly built battery factory in North China. The workers had just entered their current job position in recent years and most of them had no previous history of occupational exposure to Pb. Blood lead levels (BLLs) and leukocytes indices were detected for all participants. Cytokinesis-blocked micronucleus assay (MN; n = 675) and alkaline comet assay (% tail DNA; n = 869) were used to assess genotoxicity. Multivariate linear and Poisson regression analyses were conducted to examine associations between leukocytes indices, genotoxic biomarkers and BLLs with adjustment for covariates. Spearman correlation and mediation analyses were used to investigate relationships between NLR and genotoxicity. RESULTS: Among all the exposed workers, NLR increased with increasing BLLs. However, WBC and LMR did not change significantly. Significant and dose-dependent increases in both MN frequencies and % tail DNA were observed among groups with different exposure doses. Compared with the normal NLR group (1.48 ≤ NLR < 4.58), the high NLR group (NLR ≥ 4.58) had higher % tail DNA. In addition, there was a significant and positive association between NLR and % tail DNA among all the workers, and % tail DNA mediated 15% of the effect of Pb on increasing NLR. CONCLUSION: Our large-scale population study shows that Pb exposure increased NLR and induced genotoxicity. There was an association between elevated NLR and DNA damage. In addition, the mediation effect of % tail DNA on the relationship between BLLs and NLR provided mechanistic evidence that certain mechanisms, e.g. inflammation, may be involved in elevation of NLR from Pb exposure. Therefore, NLR may be a convenient and sensitive biomarker for indication of Pb toxicity. Further studies are needed to validate the proposed mechanism and NLR as a biomarker.

Development of a benchmark dose for lead-exposure based on its induction of micronuclei, telomere length changes and hematological toxicity.

BACKGROUND: Excessive lead exposure is associated with adverse health effects. However, there is a lack of systematic investigation using large populations to ascertain acceptable exposure limits. OBJECTIVES: Our study was aimed to identify human exposure-response relationships between lead exposure and health-related outcomes, and to determine a benchmark dose (BMD). METHODS: A total of 1896 participants from a lead-acid battery plant were recruited. Blood lead levels (BLLs) were detected for all participants. Hematological parameters (n = 1896), micronuclei (MN) frequencies (n = 934), and relative telomere length (rTL) (n = 757) were also determined. Multivariate linear/Poisson regression analyses were performed to examine associations between BLLs and these health outcomes. Restricted cubic splines were used to identify dose-response relationships. Three BMD approaches were used to calculate BMD and its 95% lower confidence limit (BMDL). RESULTS: Among all participants, BLLs show a right-skewed distribution (median, 185.40 µg/L; 25th - 75th percentile, 104.63-271.70 µg/L). There existed significant differences for red blood cell (RBC), hemoglobin (Hb), MN and rTL among different BLL dose groups. After adjusting for possible confounders, all indicators were significantly associated with BLLs. Restricted cubic splines show that there were linear dose-response relationships for RBC and Hb with BLLs, while non-linear for MN and rTL. Results from the three BMD approaches indicate that the dichotomous models were better than continuous models to calculate BMD and BMDL of BLLs. The conservative BMDL obtained from RBC data was 135 for total, 104 for male and 175 µg/L for female. The corresponding BMDL obtained from Hb data was 105 for total, 116 for male and 70 µg/L for female. As for MN data, the BMDL estimate was 66 for total, 69 for male and 64 µg/L for female. Finally, the BMDL from rTL data was 35 for total, 32 for male and 43 µg/L for female. CONCLUSIONS: Our data show significant dose-response relationships between lead exposure and expressions of hematological toxicity and genotoxicity. The new BMDLs of 135 and 105 µg/L based on RBC and Hb, and even more strict level of 66 and 35 µg/L based on MN and rTL are lower than current exposure limits in China. Therefore, the four values can be considered as novel exposure limits. In addition, sex effect should be taken into account when setting occupational health standard. Considering that different biomarkers have different sensitivities, better understanding their relationships will certainly improve the current emphasis on precision health risk assessment.

PIG-A gene mutation as a genotoxicity biomarker in human population studies: An investigation in lead-exposed workers.

The rodent Pig-a gene mutation assay has demonstrated remarkable sensitivity in identifying in vivo mutagens, while much less is known about the value of the human PIG-A assay for risk assessment. To obtain more evidence of its potential as a predictive biomarker for carcinogen exposure, we investigated PIG-A mutant frequencies (MFs), along with performing the Comet assay and micronucleus (MN) test, in 267 workers occupationally exposed to lead. Multivariate Poisson regression showed that total red blood cell PIG-A MFs were significantly higher in lead-exposed workers (10.90 ± 10.7 × 10-6 ) than in a general population that we studied previously (5.25 ± 3.6 × 10-6 ) (p < .0001). In contrast, there was no increase in lymphocyte MN frequency or in DNA damage as measured by percentage comet tail intensity in whole blood cells. Current year worker blood lead levels (BLL), an exposure biomarker, were elevated (232.6 ± 104.6 µg/L, median: 225.4 µg/L); a cumulative blood lead index (CBLI) also was calculated based on a combination of current and historical worker BLL data. Chi-square testing indicated that PIG-A MFs were significantly related to CBLI (p = .0249), but independent of current year BLL (p = .4276). However, % comet tail intensity and MN frequencies were better associated with current year BLL than CBLI. This study indicates that the PIG-A assay could serve as biomarker to detect the genotoxic effects of lead exposure and demonstrates that a battery of genotoxicity biomarkers having mechanistic complementarity may be useful for comprehensively monitoring human carcinogenic risk.

Dose-related telomere damage associated with the genetic polymorphisms of cGAS/STING signaling pathway in the workers exposed by PAHs.

Telomeres are located at the end of eukaryotic chromosomes and vulnerable to exogenous chemical compounds. Exposure to coke oven emissions (COEs) leads to a dose-related telomere damage, and such chromosomal damage might trigger the cGAS/STING signaling pathway which plays an important role in immune surveillance. However, the relationship between the genetic variations in the cGAS/STING signaling pathway and telomere damage in the COEs-exposure workers has not been investigated. Therefore, we recruited 544 coke oven workers and 238 healthy control participants, and determined the level of COEs exposure, concentration of urinary 1-hydroxypyrene (1-OHPYR), genetic polymorphisms and telomere length. The results showed that the telomere length significantly decreased from the control-to high-exposure groups as defined by the external exposure level (P < 0.05). The results also indicated that STING rs7447927 CC, cGAS rs34413328 AA, and cGAS rs610913 AA could inhibit telomere shortening in the exposure group (P < 0.05), and cGAS rs34413328, urine 1-OHPYR and cumulative exposure dose (CED) had a significant association with telomere length by generalized linear model. In conclusion, telomere shortening was a combined consequence of short-term exposure, long-term exposure, and genetic variations among the COEs-exposure workers.

Effect of TRF1 rs3863242 polymorphism on telomere length in omethoate-exposed workers.

Telomere length was found to be associated with omethoate exposure and polymorphisms in certain genes among occupational workers. However, whether the polymorphisms in telomere-binding protein genes influence telomere length remains unclear. To explore the correlation between telomere length and polymorphisms in telomere-binding protein genes, telomere length in peripheral blood leukocytes was determined by real-time quantitative polymerase chain reaction in 180 omethoate-exposed workers and 115 healthy controls. Polymorphisms in 10 pairs of alleles were detected using flight mass spectrometry or polymerase chain reaction-restriction fragment length polymorphism technique. The results showed that individuals with GG genotype in TRF1 rs3863242 had longer telomere lengths than those with AG + AA genotype in the control group (p = 0.005). The multiple regression analysis suggested that both omethoate exposure (b = 0.526, p < 0.001) and TRF1 rs3863242 GG (b = 0.220, p = 0.002) were related to a longer telomere length. In conclusion, GG genotype in TRF1 rs3863242 is linked to prolongation of telomere length, and individuals with GG genotype are recommended to strengthen health protection in a Chinese occupational omethoate-exposed population.

Effects of Micronucleus Frequencies and Mitochondrial DNA Copy Numbers among Benzene-Exposed Workers in China.

To provide a more comprehensive understanding of genotoxic effects from benzene exposure, its effects on induction of mitochondrial DNA copy number (MtDNAcn) and of micronucleus (MN) were investigated using peripheral blood from workers in China. Changes in mtDNAcn and MN were determined using quantitative real-time polymerase chain reaction (PCR) and cytokinesis-block micronucleus assays (CBMN), respectively, in 58 control and 174 benzene-exposed workers in Shanghai, China. Among the exposed workers, relative mtDNAcn increased and then decreased with increasing doses of benzene exposure. Significant and dose-dependent increase in MN frequencies were observed among the different exposure groups. In addition, the relative mtDNAcn were significantly associated with the MN frequencies in the low-level exposure group (P = 0.046), but not in the high dose groups. Therefore, the mechanisms for induction of MtDNAcn and MN by benzene may be similar from exposure to low doses but different from high doses. Similar increase of MN frequencies and MtDNAcn may be due to oxidative stress induced by benzene at low concentrations, while higher concentrations may start to initiate the cell death pathway. The pathway may be associated with excessive MtDNAcn which can initiate apoptosis while MN can continue to be induced. However, the differential mechanisms need to be investigated because they may represent different levels of risk for different health consequences. On the other hand, our data indicate that induction of MtDNAcn may be a sensitive genotoxic biomarker for workers with exposure to low dose of benzene. Environ. Mol. Mutagen. 61:355-360, 2020. © 2020 Wiley Periodicals, Inc.

Identification of Three Differentially Expressed miRNAs as Potential Biomarkers for Lung Adenocarcinoma Prognosis.

OBJECTIVE: The aim of this study areto screen MicroRNAs (miRNAs) related to the prognosis of lung adenocarcinoma (LUAD) and to explore the possible molecular mechanisms. METHODS: The data for a total of 535 patients with LUAD data were downloaded from The Cancer Genome Atlas (TCGA) database. The miRNAs for LUAD prognosis were screened by both Cox risk proportional regression model and Last Absolute Shrinkage and Selection Operator (LASSO) regression model. The performances of the models were verified by time-dependent Receiver Operating Characteristic (ROC) curve. The possible biological processes linked to the miRNAs' target genes were analyzed by Gene Ontology (GO), Kyoto gene and genome encyclopedia (KEGG). RESULTS: Among 127 differentially expressed miRNAs identified from the screening analysis, there are 111 up-regulated and 16 down-regulated miRNAs. Three of them, hsa-miR-1293, hsa-miR-490 and hsa-miR- 5571, were also significantly associated with the survival of the LUAD patients. The targets of the three miRNAs are significantly enriched in systemic lupus erythematosus pathways. CONCLUSION: Hsa-miR-1293, hsa-miR-490 and hsa-miR-5571 can be potentially used as novel biomarkers for the prognosis prediction of LUAD.

Associations of blood lead levels with multiple genotoxic biomarkers among workers in China: A population-based study.

Carcinogenic effects from low doses of lead (Pb) exposure to populations have been suspected but not concluded. Therefore, a large-scale cross-sectional study was conducted by us to investigate genotoxic effects from Pb exposure during 2016-2018 in North China. Blood lead levels (BLLs) and cumulative blood lead levels (CBLLs) were measured. Multiple relevant biomarkers were used to assess genotoxicity of Pb: mitochondrial DNA copy number (mtDNAcn, n = 871), Comet Tail Intensity (n = 872), γ-H2AX (n = 345), relative telomere length (rTL, n = 757), micronuclei (MN, n = 934) and phosphatidylinositol glycan class A mutation (PIG-A, n = 362). The BLL data show right-skewed distribution, with increase of the median (P25, P75) from 17.4 (8.9, 26.4) µg/dl in 2016 to 18.5 (10.5, 27.2) µg/dl in 2017, and to 20.8 (11.3, 31.0) µg/dl in 2018. Multivariate regression analyses show that mtDNAcn was non-linearly associated with BLLs or CBLLs, i.e. decreased at low levels but increased at the higher levels. Comet and Micronuclei data show positive dose-response relationships with BLLs as well as CBLLs. γ-H2AX data show an overall increased trend with BLLs while rTL data show a shortening trend. No associations were found for PIG-A mutation with Pb exposure. Our findings indicate that current low dose exposure to Pb can still cause health hazards to occupational populations, and the mechanism may be via the induction of DNA & chromosome damage rather than via the mutagenesis pathway.

Effects of polycyclic aromatic hydrocarbon exposure and miRNA variations on peripheral blood leukocyte DNA telomere length: A cross-sectional study in Henan Province, China.

Telomeres play a major role in human aging and disease, especially in most cancers. Telomere length was shortened in workers exposed to polycyclic aromatic hydrocarbons (PAHs) and influenced by individual genetic variations in telomere-binding proteins. MicroRNAs (miRNAs) can affect the progress of messenger RNA (mRNA) transcription; however, whether polymorphisms in miRNA can act on the telomere length is still unknown. Therefore, we aimed to explore the relationships between telomere damage and genetic polymorphisms in miRNA or environmental exposure. A total of 544 coke oven workers and 238 healthy controls were recruited. After collecting peripheral blood and extracting the genomic DNA of the study subjects, the telomere length (TL) in their leucocytes was detected by a real-time quantitative polymerase chain reaction (PCR), and polymorphisms in miRNAs were genotyped using the flight mass spectrometry technique. The concentrations of the four urine OH-PAHs were determined by high performance liquid chromatography (HPLC), and the Soxhlet extraction method was used to detect the concentration of coke oven emissions (COEs) in the air. We found that the peripheral blood leucocyte DNA TL was significantly shorter in the exposure group (0.75; 0.51, 1.08) than that in the control group (1.05; 0.76, 1.44) (Z = 7.692, P < 0.001). The total cumulative exposure dose (CED), 1-hydroxypyrene, 2-hydroxynaphthalene, and 3-hydroxyphenanthrene were significantly negatively correlated with TL (r = -0.307, P < 0.001; r = -0.212, P < 0.001; r = -0.110, P = 0.025; r = -0.251, P < 0.001, respectively). MiR-145 rs353291 GG, miR-30a rs2222722 CT/CC, and miR-197 rs1889470 AA could protect the telomere end in the exposed workers (P < 0.05). The interaction between miR-197 rs1889470 and the CED had an effect on TL (ß = 0.066, P = 0.034). This is the first study to evaluate gene-environmental interactions for miRNA polymorphisms and PAH exposure in coke oven workers.

The association between polymorphisms in tankyrase gene and telomere length in omethoate-exposed workers.

Peripheral blood leukocyte telomere length in omethoate-exposed workers is related to environmental exposure and single nucleotide polymorphisms (SNPs) in genes including p21, GSTM1, miR-145, etc. However, the roles of SNPs in tankyrase (TNKS) gene in telomere length are still unknown. The aim of this study was to explore the association between SNPs in TNKS gene and telomere length in omethoate-exposed workers. Telomere length in peripheral blood leukocyte DNA from 180 omethoate-exposed workers and 115 healthy controls was measured using Real-time quantitative polymerase chain reaction (PCR). Genotyping of the selected functional and susceptible SNPs was performed by the flight mass spectrometry based on PCR and single-base extension. The analysis of covariance was performed to find effects of SNPs on telomere length. Generalized linear models were used to analyze the environment, gene, and interaction on telomere length. The results showed that telomere length in the CG + CC genotypes in rs1055328 in TNKS gene was significantly longer than that in the wild homozygous GG genotype both in exposure group (P = 0.017) and in control group (P = 0.038) after adjusting the covariates. The variables kept in the generalized linear models included omethoate-exposure (ß = 0.580, P = 0.001) and rs1055328 (CG + CC) in TNKS gene (ß = 0.339, P = 0.002). The study suggests that the prolongation of telomere length is associated with omethoate-exposure and the CG + CC genotypes in rs1055328 in TNKS gene.

Telomere length in workers was effected by omethoate exposure and interaction between smoking and p21 polymorphisms.

Omethoate is an organophosphorus pesticide that poses a major health hazard, especially DNA damage. The purpose of this study was to investigate the factors affecting telomere length in workers exposed to omethoate by analyzing the interaction between cell cycle gene polymorphism and environmental factors. The exposure group consisted of 118 workers exposed to omethoate for 8-10 years, the control group comprised 115 healthy people without occupational toxicant exposure history. The telomere length of genomic DNA from peripheral blood leucocyte was determined with real-time PCR. Polymerase chain reaction and restriction fragment length polymorphism was used to detect the polymorphisms in p53, p21 and MDM2 gene. The telomere length in the (CA + AA) genotypes for p21 rs1801270 polymorphism was longer than that in the CC genotype in control group (P = 0.015). The generalized linear model analysis indicated the interaction of the p21 rs1801270 polymorphic (CA + AA) genotypes and smoking has a significant effect on telomere length (ß = -0.258, P = 0.085). The prolongation of telomere length in omethoate-exposed workers was associated with genotypes (CA + AA) of p21 rs1801270, and interactions of (CA + AA) genotypes and smoking factor.

Benchmark dose assessment for coke oven emissions-induced telomere length effects in occupationally exposed workers in China.

Telomeres are DNA-protein structures that protect chromosome ends from degradation and fusion, which are shortened by oxidative stress, for example air pollution including benzene, toluene, Coke Oven Emissions (COEs), and so on. As a biomarker of health and disease, telomere length is associated with cardiovascular, diabetes and cancers. The aim of this study was to estimate the effects of COEs exposure on telomere length and the benchmark dose (BMD) of COEs. A total of 542 coke oven workers and 235 healthy controls without exposure to toxicants were recruited. Quantitative PCR was used to determine the telomere length in human peripheral blood leukocytes DNA. Propensity scoring was used to match coke oven workers to healthy controls. Linear regression models and trend tests were used to the relationship between COEs exposure and telomere length. Telomere length in COEs exposed group 0.764 (0.536, 1.092) was significantly shorter than that in the control group 1.064(0.762, 1.438), (P < 0.001). There were significantly dose-response relationships between COEs exposure and telomere damage with telomere length as a biomarker. A BMDL value lower than the present occupational exposure limits (OELs) of COEs exposure was evaluated using the BMD approach in coke oven workers. Our results suggested that shorter telomere length is related to occupational exposure to COEs and the level of COEs exposure lower than the current national OELs in China and many other countries could induce telomere damage.

The interaction effects of coke oven emissions exposure and metabolic enzyme Gene variants on total antioxidant capacity of workers.

OBJECTIVES: The aim of this study was to investigate the association between coke oven emissions (COEs) exposure and total antioxidant capacity (T-AOC), and to explore whether genetic variations in metabolic enzyme genes GSTT1, GSTM1, GSTP1, and CYP2E1 can affect these associations in coke oven workers. METHODS: 536 coke oven workers and 238 healthy controls were recruited. T-AOC of plasma was determined with kit. Five polymorphic loci of GSTT1 (+/-), GSTM1 (+/-), GSTP1 rs1695, CYP2E1 rs6413432 and CYP2E1 rs3813867 were detected by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: This study shows that the T-AOC in exposure group (12.02 ±â€¯4.72) was significantly lower than that in control group (15.32 ±â€¯7.19) (P < 0.01), and the COEs exposure could decrease the T-AOC of coke oven workers significantly [ß(95% CI) = -2.663 (-4.538,-0.787), P < 0.001]. The T-AOC of female was lower than that of male in exposed and control groups (P < 0.001). The T-AOC was higher in GSTM1 (-) individuals than in GSTM1 (+) individuals in the control group (P = 0.037). The T-AOC with the AG genotype in GSTP1 rs1695 polymorphism was higher than that of the GG genotype in the control group (P = 0.043). The generalized linear model results showed that the risk factors for the decrease of T-AOC include GSTT1 (+) (b = -0.999, P = 0.009), female (b = -2.875, P < 0.01), COEs-exposed (b = -2.712, P = 0.004), GSTM1 (+) (b = -1.814, P = 0.008), and interactions of GSTM1 (+) and COEs-exposed (b = 1.872, P=0.024). CONCLUSIONS: The risk factors for the decrease of T-AOC include GSTT1 (+), female, COEs-exposed, GSTM1 (+), and interactions of GSTM1 (+) and COEs-exposed.