Elevated urinary mutagenicity among those exposed to bituminous coal combustion emissions or diesel engine exhaust.

Urinary mutagenicity reflects systemic exposure to complex mixtures of genotoxic/carcinogenic agents and is linked to tumor development. Coal combustion emissions (CCE) and diesel engine exhaust (DEE) are associated with cancers of the lung and other sites, but their influence on urinary mutagenicity is unclear. We investigated associations between exposure to CCE or DEE and urinary mutagenicity. In two separate cross-sectional studies of nonsmokers, organic extracts of urine were evaluated for mutagenicity levels using strain YG1041 in the Salmonella (Ames) mutagenicity assay. First, we compared levels among 10 female bituminous (smoky) coal users from Laibin, Xuanwei, China, and 10 female anthracite (smokeless) coal users. We estimated exposure-response relationships using indoor air concentrations of two carcinogens in CCE relevant to lung cancer, 5-methylchrysene (5MC), and benzo[a]pyrene (B[a]P). Second, we compared levels among 20 highly exposed male diesel factory workers and 15 unexposed male controls; we evaluated exposure-response relationships using elemental carbon (EC) as a DEE-surrogate. Age-adjusted linear regression was used to estimate associations. Laibin smoky coal users had significantly higher average urinary mutagenicity levels compared to smokeless coal users (28.4 ± 14.0 SD vs. 0.9 ± 2.8 SD rev/ml-eq, p = 2 × 10-5 ) and a significant exposure-response relationship with 5MC (p = 7 × 10-4 ). DEE-exposed workers had significantly higher urinary mutagenicity levels compared to unexposed controls (13.0 ± 10.1 SD vs. 5.6 ± 4.4 SD rev/ml-eq, p = .02) and a significant exposure-response relationship with EC (p-trend = 2 × 10-3 ). Exposure to CCE and DEE is associated with urinary mutagenicity, suggesting systemic exposure to mutagens, potentially contributing to cancer risk and development at various sites.

A History of Cancer Research: Carcinogens and Mutagens.

Observations of the incidence of tumors among chimney sweeps in the eighteenth century and later experiments with coal tars provided early evidence that carcinogens in the environment can promote cancer. Subsequent studies of individuals exposed to radiation, work on fly genetics, and the discovery that DNA was the genetic material led to the idea that these carcinogens act by inducing mutations in DNA that change the behavior of cells and ultimately cause cancer. In this excerpt from his forthcoming book, Joe Lipsick looks back at how the concepts of mutagenesis and carcinogenesis emerged, how these converged with development of the Ames test, and how biochemistry and crystallography ultimately revealed the underlying molecular basis.

Carbon black nanoparticles induce HDAC6-mediated inflammatory responses in 16HBE cells.

Long-term inhalation of carbon black nanoparticles (CBNPs) leads to pulmonary inflammatory diseases. Histone deacetylase 6 (HDAC6) has been identified as an important regulator in the development of inflammatory disorders. However, the direct involvement of HDAC6 in CBNPs-induced pulmonary inflammatory responses remains unclear. To explore whether HDAC6 participates in CBNPs-induced pulmonary inflammation, human bronchial epithelial cell line (16HBE cells) was transfected with HDAC6 small interference RNA (siRNA) and then exposed to CBNPs at concentrations of 0, 25, and 50 µg/ml for 24 h. Intracellular HDAC6 and intraflagellar transport protein 88 (IFT88) mRNA and protein were determined by real-time polymerase chain reaction and Western blot, respectively. The secretions of inflammatory cytokines including interleukin (IL)-8, tumor necrosis factor (TNF)-α, IL-6, and IL-1ß were measured by enzyme-linked immunosorbent assay. CBNPs induced a significant increase in the expressions of IL-8 and IL-6, accompanied by a high level of intracellular HDAC6 mRNA when compared with a blank control group (p < 0.05). However, there were no significant changes in the levels of TNF-α secretion, intracellular HDAC6 and IFT88 protein induced by CBNPs (p > 0.05). The HDAC6 mRNA expression was significantly suppressed in HDAC6 siRNA-transfected cells (p < 0.05). The secretions of IL-8, TNF-α, and IL-6 were significantly less in HDAC6 siRNA-transfected cells than that in normal 16HBE cells with exposure to 25 or 50 µg/ml of CBNPs, but intracellular IFT88 mRNA expression was markedly increased in HDAC6 siRNA-transfected cells when compared with normal 16HBE cells exposed to 50 µg/ml of CBNPs (all p < 0.05). Downregulation of the HDAC6 gene inhibits CBNPs-induced inflammatory responses in bronchial epithelial cells, partially through regulating IFT88 expression. It is suggested that CBNPs may trigger inflammatory responses in bronchial epithelial cells by an HDAC6/IFT88-dependent pathway.

Occupational benzene exposure and the risk of genetic damage: a systematic review and meta-analysis.

BACKGROUND: Benzene, an important component of organic solvents, is commonly used in industry. Meanwhile, benzene is a human carcinogen leading to leukemia. Although the links between benzene and various types of genetic damage indicators have been evaluated in several studies, but their results remain inconsistent. So we conducted a meta-analysis, and to explore the influence of low concentration benzene exposure on workers' genetic damage indicators using 3.25 mg/m3 as the boundary value, in order to provide a basis for improved prevention and control of the harm from benzene exposure to the occupational population. METHODS: We conducted a search of five databases, including Pub Med, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang Data and Chongqing VIP, to identify relevant articles up to December 25, 2018. Two researchers independently extracted and evaluated the data according to the inclusion and exclusion criteria of the literature. The imported articles were managed by Endnote X7, and the data were extracted and sorted by Excel 2013. We utilized Stata 12.0 software to perform the meta-analysis in the present study. RESULTS: A total of 68 eligible articles were finally included for the synthetic analyses. The meta-analysis results showed that occupational benzene exposure led to significantly increased Micronucleus (MN) frequency, Sister chromatid exchange (SCE) frequency, Chromosome aberration (CA) frequency, Olive Tail moment (OTM), Tail moment (TM), Tail length (TL), and Tail DNA% (T DNA%) compared to the control group (P < 0.05), and the pooled effect value estimates were 1.36, 0.98, 0.76, 1.06, 0.96, 1.78, and 1.42, respectively. Subsequent analysis of the effect of low concentration benzene exposure on genetic damage found significantly increased MN frequency increased compared with the control group (P < 0.05). CONCLUSIONS: Occupational benzene exposure can affect multiple genetic damage indicators. Even at an exposure concentration lower than 3.25 mg/m3, benzene exposure has genotoxicity. These data provide an important scientific basis for the further revision of occupational disease prevention strategies. At the same time, increased attention should be focused on the health monitoring of the occupational population exposed to benzene, and health management should be strengthened to improve the health of the occupational population.

Polymorphism in GRHL2 gene may contribute to noise-induced hearing loss susceptibility: a meta-analysis / Polimorfismo no gene GRHL2 pode contribuir para a suscetibilidade à perda auditivainduzida por ruído: uma metanálise

Abstract Instruction: Noise-induced hearing loss is a leading occupational disease caused by gene-environment interaction. The Grainy Like 2, GRHL2, is a candidate gene. In this regard, many studies have evaluated the association between GRHL2 and noise-induced hearing loss, although the results are ambiguous and conflicting. Objective: The purpose of this study was to identify a precise estimation of the association between rs3735715 polymorphism in GRHL2 gene and susceptibility of noise-induced hearing loss. Methods: A comprehensive search was performed to collect data up to July 8, 2018. Finally, 4 eligible articles were included in this meta-analysis comprising 2410 subjects. The pooled odds ratios with 95% confidence intervals were used to evaluate the strength of the association. Results: Significant association was found in the overall population in the dominant model (GA/AA vs. GG, odds ratio = 0.707, 95% confidence interval = 0.594-0.841) and allele model (G allele vs. A allele, odds ratio = 1.189, 95% confidence interval = 1.062-1.333). When stratified by source of the subjects, we also found association between rs3735715 and noise-induced hearing loss risk in the dominant model (GA/AA vs. GG, odds ratio = 0.634, 95% confidence interval = 0.514-0.783) and allele model (G allele vs. A allele, odds ratio = 1.206, 95% confidence interval = 1.054-1.379). Conclusion: Rs3735715 polymorphism in GRHL2 gene may influence the susceptibility of noise-induced hearing loss. Additional large, well-designed and functional studies are needed to confirm this association in different populations.

Resumo Introdução: Perda auditiva induzida por ruído é uma das principais doenças ocupacionais causadas pela interação gene-ambiente. O Grainy Like 2, ou GRHL2 é um gene que tem sido considerado como candidato. Nesse sentido, muitos estudos avaliaram a associação entre o GRHL2 e perda auditiva induzida por ruído, embora os resultados sejam ambíguos e conflitantes. Objetivo: Identificar uma estimativa precisa da associação entre o polimorfismo rs3735715 no gene GRHL2 e a suscetibilidade à perda auditiva induzida por ruído. Método: Uma pesquisa abrangente foi feita para coletar dados até 8 de julho de 2018. No fim, quatro artigos elegíveis foram incluídos nesta metanálise, abrangeram 2.410 indivíduos. As odds ratios agrupadas com intervalos de confiança de 95% foram usadas para avaliar a força da associação. Resultados: Uma associação significante foi encontrada na população geral no modelo de dominância (GA/AA vs. GG, odds ratio = 0,707, intervalo de confiança 95% = 0,594-0,841) e modelo de alelo (alelo G vs. alelo A; odds ratio = 1,189, intervalo de confiança 95% = 1,062 a 1,333). Quando estratificados pelo local de trabalho dos indivíduos, também encontramos associação entre rs3735715 e risco de perda auditiva induzida por ruído no modelo de dominância (GA/AA vs. GG, odds ratio = 0,634, intervalo de confiança 95% = 0,514 ± 0,783) e modelo de alelo (alelo G vs. alelo A; odds ratio = 1,206, intervalo de confiança 95% = 1,054- 1,379). Conclusão: O polimorfismo Rs3735715 no gene GRHL2 pode influenciar a suscetibilidade à perda auditiva induzida por ruído. Estudos adicionais, amplos, bem desenhados e funcionais são necessários para confirmar essa associação em diferentes populações.

Effects of Vitamin D Receptor, Metallothionein 1A, and 2A Gene Polymorphisms on Toxicity of the Peripheral Nervous System in Chronically Lead-Exposed Workers.

Chronic exposure to lead is neurotoxic to the human peripheral sensory system. Variant vitamin D receptor (VDR) genes and polymorphisms of metallothioneins (MTs) are associated with different outcomes following lead toxicity. However, no evidence of a relationship between lead neurotoxicity and polymorphisms has previously been presented. In this study, we investigated the relationship between the polymorphisms of VDR, MT1A, and MT2A genes and lead toxicity following chronic occupational lead exposure. We measured vibration perception thresholds (VPT) and current perception thresholds (CPT) in 181 workers annually for five years. The outcome variables were correlated to the subject's index of long-term lead exposure. Polymorphisms of VDR, MT1A, and MT2A were defined. The potential confounders, including age, sex, height, smoking, alcohol consumption, and working life span, were also collected and analyzed using linear regression. The regression coefficients of some gene polymorphisms were at least 20 times larger than regression coefficients of time-weighted index of cumulative blood lead (TWICL) measures. All regression coefficients of TWICL increased slightly. MT1A rs11640851 (AA/CC) was associated with a statistically significant difference in all neurological outcomes except hand and foot VPT. MT1A rs8052394 was associated with statistically significant differences in hand and foot CPT 2000 Hz. In MT2A rs10636, those with the C allele showed a greater effect on hand CPT than those with the G allele. Among the VDR gene polymorphisms, the Apa rs7975232 (CC/AA) single nucleotide polymorphism was associated with the greatest difference in hand CPT. MT2A rs28366003 appeared to have a neural protective effect, whereas Apa (rs7975232) of VDR and MT2A rs10636 increased the neurotoxicity as measured by CPT in the hands. MT1A rs8052394 had a protective effect on large myelinated nerves. MT1A rs11640851 was associated with susceptibility to neurotoxicity.

Interactions between the MMP-3 gene rs591058 polymorphism and occupational risk factors contribute to the increased risk for lumbar disk herniation: A case-control study.

OBJECTIVE: Lumbar disk herniation (LDH) is a complex condition based on lumbar disk degeneration (LDD). Previous studies have shown that genetic factors are highly associated with the severity and risk for LDH. This case-control study was aimed to evaluate the association between the matrix metalloproteinase (MMP)-3 gene rs591058 C/T polymorphism and LDH risk in a southern Chinese population. METHODS: A total of 231 LDH patients and 312 healthy controls were recruited in this study. Genotyping was analyzed using a standard polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). RESULTS: It was observed that TT genotype or T allele carriers of the MMP-3 gene rs591058 C/T polymorphism was more likely associated with an increased risk for LDH. Subgroup analyses showed the following characteristics increased the risk for LDH: female sex; cigarette smoking; and alcohol consumption. Furthermore, individuals with high whole body vibration, bending/twisting, and lifting were associated with an increased risk for LDH. CONCLUSION: Taken together, these data indicated that the MMP-3 gene rs591058 C/T polymorphism was associated with an increased risk for LDH. The MMP-3 gene rs591058 C/T polymorphism might serve as a clinical indicator and marker for LDH risk in the Chinese population.

Up-regulation of DNMT3b contributes to HOTAIRM1 silencing via DNA hypermethylation in cells transformed by long-term exposure to hydroquinone and workers exposed to benzene.

Benzene exposure is a risk factor of acute myeloid leukemia (AML), during such carcinogenesis long non-coding RNAs (lncRNAs) are important epigenetic regulators. HOTAIRM1 (HOXA transcript antisense RNA, myeloid-specific 1) plays an indispensable role in the development of AML. Hydroquinone (HQ) is one major metabolite of benzene and its ideal replacement in toxicology research. But the influence of benzene or HQ on HOTAIRM1 expression in AML associated pathway is still unclear. In the TK6 cells with short-term exposure to HQ (HQ-ST cells) or long term HQ exposure induced malignant transformed TK6 cells (HQ-MT cells), the relationship between DNMT3b and HOTAIRM1 was explored. Comparing to counterparts, HOTAIRM1 expression was increased firstly and then decreased in HQ-ST cells, and definitely decreased in HQ-MT cells; while the expression change tendency of DNMT3b was in contrast to that of HOTAIRM1. Moreover, the average HOTAIRM1 expression of 17 paired workers being exposed to benzene within 1.5 years was increased, but that of the remaining 92 paired workers with longer exposure time was decreased. Furthermore, in 5-AzaC (DNA methyltransferase inhibitor) or TSA (histone deacetylation inhibitor) treated HQ-MT cells, the expression of HOTAIRM1 was restored by reduced DNA promoter methylation levels. HQ-MT cells with DNMT3b knockout by CRISPR/Cas9 displayed the promoter hypomethylation and the increase of HOTAIRM1, also confirmed in benzene exposure workers. These suggest that long term exposure to HQ or benzene might induce the increase of DNMT3b expression and the promoter hypermethylation to silence the expression of HOTAIRM1, a possible tumor-suppressor in the AML associated carcinogenesis pathway.

Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation.

Liver cancer is associated with genetic mutations caused by environmental exposures, including occupational exposure to alpha radiation emitted by plutonium. We used whole exome sequencing (WES) to characterize somatic mutations in 3 histologically distinct primary liver tumors (angiosarcoma of the liver (ASL), cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC)) from Mayak worker subjects occupationally exposed to ionizing radiation (IR) to investigate the contribution of IR to the mutational landscape of liver cancer. DNA sequence analysis revealed these tumors harbor an excess of deletions, with a deletions:substitutions ratio similar to that previously reported in radiation-associated tumors. These tumors were also enriched for clustered mutations, a signature of radiation exposure. Multiple tumors displayed similarities in abrogated gene pathways including actin cytoskeletal signaling and DNA double-strand break (DSB) repair. WES identified novel candidate driver genes in ASL involved in angiogenesis and PIK3CA/AKT/mTOR signaling. We confirmed known driver genes of CCA, and identified candidate driver genes involved in chromatin remodeling. In HCC tumors we validated known driver genes, and identified novel putative driver genes involved in Wnt/ß-catenin signaling, chromatin remodeling, PIK3CA/AKT/mTOR signaling, and angiogenesis. This pilot study identifies several novel candidate driver mutations that are likely to be caused by IR exposure, and provides the first data on the mutational landscape of liver cancer after IR exposure.

The Association of Serum TNF-α Levels and Blood Multi-Elements Modified by TNF-α Gene Polymorphisms in Metal Industrial Workers.

Health of the metal industrial workers should be a noteworthy issue due to the hazard ofchronic exposure to metals or toxic elements. The interactions among multiple elements aresophisticated and may differ from person to person. Tumor necrosis factor-α (TNF-α) genepolymorphisms were supposed to be involved with the interactions because TNF-α plays animportant role in inflammation, a mechanism by which toxic elements cause threats to humanhealth. This research aimed to analyze the influence of TNF-αgene polymorphisms and multielementson serum TNF-α level. Blood multi-elements concentrations (lead, cadmium, arsenic,selenium, cobalt, copper, and zinc), serum TNF-α level, and TNF-α single nucleotidepolymorphisms (SNPs), including -238G > A (rs361525), -308G > A (rs1800629), -857C > T(rs1799724), -863C > A (rs1800630), and -1031T > C (rs1799964), were measured in 462 metalindustrial workers. We applied mixed-effect models to analyze the interactions among multielementsand TNF-α SNPs. Blood concentration of all elements were positively associated withserum TNF-α level, and the effects may be modified by TNF-α gene polymorphisms. Our studyrevealed that TNF-α -308A/A and -1031C/C may be susceptible genotypes, and thus we suggestthat those workers should take preventive measures against metal toxicity.

Absence of mutations in the human interferon alpha-2b gene in workers chronically exposed to ionising radiation.

Individuals chronically exposed to low-level ionising radiation (IR) run the risk of harmful and long-term adverse health effects, including gene mutations and cancer development. The search for reliable biomarkers of IR exposure in human population is still of great interest, as they may have a great implementation potential for the surveillance of occupationally exposed individuals. In this context, and considering previous literature, this study aimed to identify mutations in the human interferon alpha-2b (hIFNα-2b) as a potential biomarker of occupational chronic low-dose IR exposure linking low-IR exposure to the effects on haematopoiesis and reduced immunity. The analysis was performed in the genomic DNA of 51 uranium miners and 38 controls from Kazakhstan, and in 21 medical radiology workers and 21 controls from Italy. hIFNα-2b gene mutations were analysed with the real-time polymerase chain reaction (PCR) or Sanger sequencing. However, none of the investigated workers had the hIFNα-2b mutation. This finding highlights the need for further research to identify biomarkers for early detection of health effects associated with chronic low-dose IR exposure.

Impact of occupational cadmium exposure on bone in sewage workers.

Cadmium (Cd) is one of the environmental risk factors for bone loss. The present study included 40 sewage workers occupationally exposed to Cd. Forty nonexposed men were included as a control group. Current smokers represented 65% and 47.5% of the exposed and control groups, respectively. The study aimed to investigate the hazard of occupational Cd exposure on bone health. This was achieved through measuring serum and urinary Cd, and calcium (Ca), in addition to serum osteoprotegerin (OPG) and estrogen receptor-α gene. Results showed significant elevation in serum Cd, OPG, and urinary Ca levels in the exposed compared to the controls. Bony aches and joint pain were more prevalent among the exposed workers. Serum and urinary Cd increased in exposed smokers relative to control smokers. Also, serum OPG levels showed significant rise among exposed smoker and nonsmoker compared to control smoker and nonsmoker groups. Serum Cd level increased significantly in PP and pp genotypes in exposed workers compared to controls, while elevated levels of serum OPG was observed in PP and Pp genotypes in exposed workers relative to controls. Urinary Cd exhibited significant rise in both PP and pp genotypes in exposed workers, while Ca excretion was elevated in pp genotype only. The study reflected an association of genetic predisposition and Cd exposure in progression of osteoporosis. Further research is needed to explain the mechanisms of Cd impact on bone. The role of smoking is important and hence smoking cessation programs are essential for sewage workers.

Genetic variation in Wnt/ß-catenin and ER signalling pathways in female and male elite dancers and its associations with low bone mineral density: a cross-section and longitudinal study.

The association of genetic polymorphisms with low bone mineral density in elite athletes have not been considered previously. The present study found that bone mass phenotypes in elite and pre-elite dancers are related to genetic variants at the Wnt/ß-catenin and ER pathways. INTRODUCTION: Some athletes (e.g. gymnasts, dancers, swimmers) are at increased risk for low bone mineral density (BMD) which, if untreated, can lead to osteoporosis. To investigate the association of genetic polymorphisms in the oestrogen receptor (ER) and the Wnt/ß-catenin signalling pathways with low BMD in elite and pre-elite dancers (impact sport athletes). METHODS: The study included three phases: (1) 151 elite and pre-elite dancers were screened for the presence of low BMD and traditional osteoporosis risk factors (low body weight, menstrual disturbances, low energy availability); (2) a genetic association study was conducted in 151 elite and pre-elite dancers and age- and sex- controls; (3) serum sclerostin was measured in 101 pre-elite dancers and age- and sex-matched controls within a 3-year period. RESULTS: Eighty dancers revealed low BMD: 56.3% had at least one traditional osteoporosis risk factor, whereas 28.6% did not display any risk factor (37.2% revealed traditional osteoporosis risk factors, but had normal BMD). Body weight, menstrual disturbances and energy availability did not fully predict bone mass acquisition. Instead, genetic polymorphisms in the ER and Wnt/ß-catenin pathways were found to be risk factors for low BMD in elite dancers. Sclerostin was significantly increased in dancers compared to controls during the 3-year follow-up (p < 0.05). CONCLUSIONS: Elite and pre-elite dancers demonstrate high prevalence of low BMD, which is likely related to genetic variants at the Wnt/ß-catenin and ER pathways and not to factors usually associated with BMD in athletes (body weight, menstrual disturbances, energy deficiency).

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

Aberrant DNA Methylation of Two Tumor Suppressor Genes, p14ARF and p15INK4b, after Chronic Occupational Exposure to Low Level of Benzene.

BACKGROUND: Exposure to benzene would be associated with many diseases including leukemia. Epigenetic alterations seem to be among the main mechanisms involved. OBJECTIVE: To determine if chronic occupational exposure to low level of benzene would be associated with DNA methylation. METHODS: Global DNA methylation and promoter-specific methylation of the two tumor suppressor genes, p14ARF and p15INK4b, were assessed employing methylation-specific PCR using the DNA extracted from 40 petrochemical workers exposed to ambient benzene levels of <1 ppm, and 31 office workers not exposed to benzene or its derivatives. RESULTS: While an increase in global DNA methylation of 5% in p14ARF (p=0.501) and 28% in p15INK4b (p=0.02) genes was observed in the exposed group, no hypermethylation in either of the studied genes was observed in the unexposed group. No significant association was found between the frequency of aberrant methylation and either of age, work experience, and smoking habit in the exposed group. CONCLUSION: Chronic occupational exposure to lower than the permissible exposure limit of benzene may still result in DNA methylation of tumor suppressor genes that may ultimately lead to development of cancer.

Impact of Occupational Exposures and Genetic Polymorphisms on Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer.

Introduction: Additional or better markers are needed to guide the clinical monitoring of patients with non-muscle-invasive bladder cancer (NMIBC). Aim: To investigate the influence of occupational exposures and genetic polymorphisms on recurrence and progression of NMIBC. Methods: The study includes 160 NMIBC patients. We collected on questionnaire information on demographic variables, lifetime smoking history, lifetime history of occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons. Genetic polymorphism (glutathione S-transferase M1; T1; P1 (GSTM1; GSTT1; GSTP1); N-acetyltransferase 1; 2 (NAT1; NAT2); cytochrome P450 1B1 (CYP1B1); sulfotransferase 1A1 (SULT1A1); myeloperoxidase (MPO); catechol-O-methyltransferase (COMT); manganese superoxide dismutase (MnSOD); NAD(P)H:quinone oxidoreductase (NQO1); X-ray repair cross-complementing group 1; 3 (XRCC1; XRCC3) and xeroderma pigmentosum complementation group (XPD)) was assessed in peripheral blood lymphocytes. DNA adducts were evaluated by 32P-postlabeling. Predictors of recurrence (histological confirmation of a newly found bladder tumor) and progression (transition of tumor from low-grade to high-grade and/or increase in TNM stage) were identified by multivariate Cox proportional hazard regression with stepwise backward selection of independent variables. Hazard ratios (HR) with 95% confidence interval (95%CI) and two-tail probability of error (p-value) were estimated. Results: The risk of BC progression decreased with the homozygous genotype "ValVal" of both COMT and MnSOD (HR = 0.195; 95%CI = 0.060 to 0.623; p = 0.006). The results on BC recurrence were of borderline significance. No occupational exposure influenced recurrence or progression. Conclusion: Our results are supported by experimental evidence of a plausible mechanism between cause (ValVal genotype of both MnSOD and COMT) and effect (decreased progression of tumor in NMIBC patients). The genetic polymorphisms associated with better prognosis may be used in clinic to guide selection of treatment for patients initially diagnosed with NMIBC. However, external validation studies are required.

MicroRNA Changes in Firefighters.

OBJECTIVES: Firefighters have elevated cancer incidence and mortality rates. MicroRNAs play prominent roles in carcinogenesis, but have not been previously evaluated in firefighters. METHODS: Blood from 52 incumbent and 45 new recruit nonsmoking firefighters was analyzed for microRNA expression, and the results adjusted for age, obesity, ethnicity, and multiple comparisons. RESULTS: Nine microRNAs were identified with at least a 1.5-fold significant difference between groups. All six microRNAs with decreased expression in incumbent firefighters have been reported to have tumor suppressor activity or are associated with cancer survival, and two of the three microRNAs with increased expression in incumbent firefighters have activities consistent with cancer promotion, with the remaining microRNA associated with neurological disease. CONCLUSION: Incumbent firefighters showed differential microRNA expression compared with new recruits, providing potential mechanisms for increased cancer risk in firefighters.

Shanghai Health Study (2001-2009): What was learned about benzene health effects?

The Shanghai Health Study (SHS) was a large epidemiology study conducted as a joint effort between the University of Colorado and Fudan University in Shanghai, China. The study was funded by members of the American Petroleum Institute between 2001 and 2009 and was designed to evaluate the human health effects associated with benzene exposure. Two arms of the SHS included: an occupational-based molecular epidemiology study and several hospital-based case control studies. Consistent with historical literature, following sufficient exposure to relatively high airborne concentrations and years of exposure, the SHS concluded that exposure to benzene resulted in an increased risk of various blood and bone marrow abnormalities such as benzene poisoning, aplastic anemia (AA), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). Non-Hodgkin lymphoma (NHL) was not significantly increased for the exposures examined in this study. Perhaps the most important contribution of the SHS was furthering our understanding of the mechanism of benzene-induced bone marrow toxicity and the importance of identifying the proper subset of MDS relevant to benzene. Investigators found that benzene-exposed workers exhibited bone marrow morphology consistent with an immune-mediated inflammatory response. Contrary to historic reports, no consistent pattern of cytogenetic abnormalities was identified in these workers. Taken together, findings from SHS provided evidence that the mechanism for benzene-induced bone marrow damage was not initiated by chromosome abnormalities. Instead, chronic inflammation, followed by an immune-mediated response, is likely to play a more significant role in benzene-induced disease initiation and progression than previously thought.

Analysis of serum microRNA expression in male workers with occupational noise-induced hearing loss

Occupational noise-induced hearing loss (ONIHL) is a prevalent occupational disorder that impairs auditory function in workers exposed to prolonged noise. However, serum microRNA expression in ONIHL subjects has not yet been studied. We aimed to compare the serum microRNA expression profiles in male workers of ONIHL subjects and controls. MicroRNA microarray analysis revealed that four serum microRNAs were differentially expressed between controls (n=3) and ONIHL subjects (n=3). Among these microRNAs, three were upregulated (hsa-miR-3162-5p, hsa-miR-4484, hsa-miR-1229-5p) and one was downregulated (hsa-miR-4652-3p) in the ONIHL group (fold change >1.5 and Pbon value <0.05). Real time quantitative PCR was conducted for validation of the microRNA expression. Significantly increased serum levels of miR-1229-5p were found in ONIHL subjects compared to controls (n=10 for each group; P<0.05). A total of 659 (27.0%) genes were predicted as the target genes of miR-1229-5p. These genes were involved in various pathways, such as mitogen-activated protein kinase (MAPK) signaling pathway. Overexpression of miR-1229-5p dramatically inhibited the luciferase activity of 3′ UTR segment of MAPK1 (P<0.01). Compared to the negative control, HEK293T cells expressing miR-1229-5p mimics showed a significant decline in mRNA levels of MAPK1 (P<0.05). This preliminary study indicated that serum miR-1229-5p was significantly elevated in ONIHL subjects. Increased miR-1229-5p may participate in the pathogenesis of ONIHL through repressing MAPK1 signaling.