Genetic risk for obesity and the effectiveness of the ChooseWell 365 workplace intervention to prevent weight gain and improve dietary choices.

BACKGROUND: It is unknown whether behavioral interventions to improve diet are effective in people with a genetic predisposition to obesity. OBJECTIVES: To examine associations between BMI genetic risk and changes in weight and workplace purchases by employees participating in a randomized controlled trial of an automated behavioral workplace intervention to promote healthy food choices. METHODS: Participants were hospital employees enrolled in a 12-mo intervention followed by a 12-mo follow-up. Hospital cafeterias utilized a traffic-light labeling system (e.g., green = healthy, red = unhealthy) that was used to calculate a validated Healthy Purchasing Score (HPS; higher = healthier). A weighted genome-wide BMI genetic score was generated by summing BMI-increasing alleles. RESULTS: The study included 397 adults of European ancestry (mean age, 44.9 y; 80.9% female). Participants in the highest genetic quartile (Q4) had a lower HPS and higher purchases of red-labeled items relative to participants in the lowest quartile (Q1) at baseline [Q4-Q1 Beta HPS, -4.66 (95% CI, -8.01 to -1.32); red-labeled items, 4.26% (95% CI, 1.45%-7.07%)] and at the 12-mo [HPS, -3.96 (95% CI, -7.5 to -0.41); red-labeled items, 3.20% (95% CI, 0.31%-6.09%)] and 24-mo [HPS, -3.70 (95% CI, -7.40 to 0.00); red-labeled items, 3.48% (95% CI, 0.54%-6.41%)] follow-up periods. In the intervention group, increases in HPS were similar in Q4 and Q1 at 12 mo (Q4-Q1 Beta, 1.04; 95% CI, -2.42 to 4.50). At the 24-mo follow-up, the change in BMI from baseline was similar between Q4 and Q1 (0.17 kg/m2; 95% CI, -0.55 to 0.89 kg/m2) in the intervention group, but higher in Q4 than Q1 (1.20 kg/m2; 95% CI, 0.26-2.13 kg/m2) in the control group. No interaction was evident between the treatment arm and genetic score for BMI or HPS. CONCLUSIONS: Having a high BMI genetic risk was associated with greater increases in BMI and lower quality purchases over 2 y. The 12-mo behavioral intervention improved employees' food choices, regardless of the genetic burden, and may have attenuated weight gain conferred by having the genetic risk.

Individual DNA Methylation Pattern Shifts in Nanoparticles-Exposed Workers Analyzed in Four Consecutive Years.

A DNA methylation pattern represents an original plan of the function settings of individual cells and tissues. The basic strategies of its development and changes during the human lifetime are known, but the details related to its modification over the years on an individual basis have not yet been studied. Moreover, current evidence shows that environmental exposure could generate changes in DNA methylation settings and, subsequently, the function of genes. In this study, we analyzed the effect of chronic exposure to nanoparticles (NP) in occupationally exposed workers repeatedly sampled in four consecutive years (2016-2019). A detailed methylation pattern analysis of 14 persons (10 exposed and 4 controls) was performed on an individual basis. A microarray-based approach using chips, allowing the assessment of more than 850 K CpG loci, was used. Individual DNA methylation patterns were compared by principal component analysis (PCA). The results show the shift in DNA methylation patterns in individual years in all the exposed and control subjects. The overall range of differences varied between the years in individual persons. The differences between the first and last year of examination (a three-year time period) seem to be consistently greater in the NP-exposed subjects in comparison with the controls. The selected 14 most differently methylated cg loci were relatively stable in the chronically exposed subjects. In summary, the specific type of long-term exposure can contribute to the fixing of relevant epigenetic changes related to a specific environment as, e.g., NP inhalation.

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.

Genetic association study between TAB2 polymorphisms and noise-induced-hearing-loss in a Han Chinese population.

Noise-induced-hearing-loss(NIHL) is a common occupational disease caused by various environmental and biological factors. To investigate the association between TAB2 and the susceptibility of NIHL of people exposed to occupational environments, a genetic association study was performed on selected companies with 588 cases and 537 healthy control subjects. Five selected single nucleotide polymorphisms (SNPs) in TAB2,incoluding rs2744434, rs521845, rs652921, rs7896, rs9485372, were genotyped after a collection of DNA samples. Evident differences in participants between the case group and the control group reveals the result that people with the TAB2 has a high probability of getting NIHL. The results show that rs521845 is deeply associated with the risk of NIHL and is available for the diagnosis in the future.

Environmental and Genetic Factors in the Pathogenesis of COPD in the Road-Working Population.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a typical heterogeneous condition caused by environmental and genetic risk factors. OBJECTIVES: We investigated extrinsic (environmental) and intrinsic (genetic) factors contributing to the development of COPD in a nonsmoker road-working population in Northeast China. METHOD: The target population was divided into a COPD group and an exposed control group. Another healthy nonroad working nonsmoker control group was also included for environmental factor comparison. Peripheral blood was collected and analyzed using inductively coupled plasma mass spectrometry for inorganic elements of PM2.5, and microarray, rt-PCR, and Multiplex ELISA for genetic factors. RESULTS: Forty-three COPD road workers, thirty-nine non-COPD road workers, and 52 age and gender-matched healthy nonroad workers were enrolled. There were significantly higher levels in all 24 inorganic elements in the COPD group compared with the healthy control group except potassium and manganese, while the majority of inorganic elements were similar between the COPD group and the exposed control group except in aluminum and cobalt. There were 39 genes showing significant differences between the COPD group and the exposed control group. Collagen, type XV, alpha 1 (COL15A1), Meis homeobox 1 (MEIS1), carbonyl reductase 3 (CBR3), and amine oxidase, copper containing 3 (AOC3) were confirmed by rt-PCR to be differentially expressed. Their correlations with blood cytokines were also evaluated. CONCLUSIONS: Aluminum might contribute to the development of COPD in the road-working population. CBR3 and AOC3 seem expressed in different patterns than previously reported, evidenced by their correlation with proinflammatory and anti-inflammatory cytokines.

Biomonitoring of workers employed in a titanium dioxide production plant: Use of buccal micronucleus cytome assay as noninvasive biomarker to evaluate genotoxic and cytotoxic effects.

We aimed to evaluate whether TiO2 production process induces genotoxic and cytotoxic effects on the first target organ of inhalable particles by a sensitive and noninvasive biomarker of effect. Final aim was to find a useful and suitable tool to assess and manage the risk of TiO2 occupational exposure. We enrolled 40 workers employed in TiO2 production, 5 office workers, and 18 external controls. Buccal micronucleus cytome assay (BMCyt assay) was applied because it allows to evaluate micronucleus (MN), nuclear buds (NB), and broken eggs (BE) indicating the presence of chromosomal instability and gene amplification and binucleated cells (BIN), karyolytic cells (KL), and condensed chromatin (CC) indicating cytokinesis defect or arrest, cell death and apoptosis respectively. We characterized the exposure measuring inhalable and respirable particles by personal monitoring. BMCyt-assay showed in exposed workers compared with external controls a higher value of MN frequency (2.57 vs. 0.05‰, p < .001) and MN positivity, evaluated as percentage of subjects with MN frequency higher than a 1.5‰ cut-off value (52.5 vs. 0%). We also found in exposed workers higher frequency of BE + NB (2.41 vs. 0.22‰, p = .002), BIN (9.45 vs. 8.44‰, p = .047) and CC (1.80 vs. 0.21, p = .001) than in controls. Moreover, we found a relationship between personal monitoring results and presence of MN and other cellular anomalies. This study demonstrates induction of genotoxic and cytotoxic effects on buccal cells of workers involved in TiO2 production, suggesting the suitability of BMCyt assay as tool for risk assessment and management of TiO2 exposure.

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.

Investigation of intra-hospital SARS-CoV-2 transmission using nanopore whole-genome sequencing.

BACKGROUND: During the SARS-CoV-2 pandemic, healthcare workers (HCWs) are being exposed to infection both at work and in their communities. Determining where HCWs might have been infected is challenging based on epidemiological data alone. At Akershus University Hospital, Norway, several clusters of possible intra-hospital SARS-CoV-2 transmission were identified based on routine contact tracing. AIM: To determine whether clusters of suspected intra-hospital SARS-CoV-2 transmission could be resolved by combining whole genome sequencing (WGS) of SARS-CoV-2 with contact tracing data. METHODS: Epidemiological data were collected during routine contact tracing of polymerase chain reaction-confirmed SARS-CoV-2-positive HCWs. Possible outbreaks were identified as wards with two or more infected HCWs defined as close contacts who tested positive for SARS-CoV-2 less than three weeks apart. Viral RNA from naso-/oropharyngeal samples underwent nanopore sequencing in direct compliance to the ARTIC Network protocol. FINDINGS: Five outbreaks were suspected from contact tracing. Viral consensus sequences from 24 HCWs, two patients, and seven anonymous samples were analysed. Two outbreaks were confirmed, one refuted, and two remained undetermined. One new potential outbreak was discovered. CONCLUSION: Combined with epidemiological data, nanopore WGS was a useful tool for investigating intra-hospital SARS-CoV-2 transmission. WGS helped to resolve questions about possible outbreaks and to guide local infection prevention and control measures.

Exertional Rhabdomyolysis and Sickle Cell Trait Status in the U.S. Air Force, January 2009-December 2018.

Sickle cell trait (SCT) is associated with incident exertional rhabdomyolysis, but its effect on disease progression and severity is poorly understood. Of 377 exertional rhabdomyolysis cases diagnosed between 2009 and 2018 in the active component of the U.S. Air Force, 200 had records available for chart review, and 185 of these had known SCT status. Pre- and post-event data were stratified by SCT status, and serum chemistry changes among SCT-positive (n=11) and SCT-negative (n=174) airmen were compared using Wilcoxon-Mann-Whitney tests. Of the 200 cases with records available for chart review, 110 (55.0%) were hospitalized; 98 (56.3%) of the 174 who were SCT-negative were hospitalized. Also hospitalized were 4 (36.4%) of the 11 who were SCT-positive, and 8 (53.3%) of the 15 with unknown SCT status. Of the 7 airmen who were admitted to intensive care, 4 required hemodialysis, and 1 underwent a fasciotomy; all 7 were SCT-negative. Alterations in creatine kinase, potassium, creatinine, troponin I, and hemoglobin were statistically equivalent between those with and without SCT. Providers should maintain a high index of suspicion for exertional rhabdomyolysis, especially in warm climates and in the context of high-intensity activities, but should not presume that the presence of SCT portends a higher risk of complications or worse clinical outcomes.

The relationship between occupational stress, musculoskeletal disorders and the mental health of coal miners: The interaction between BDNF gene, TPH2 gene polymorphism and the environment.

OBJECTIVE: Mental disorders are prevalent among the population and seriously endanger people's working ability as well as their physical and mental health. This study employed stratified cluster random sampling to examine occupational stress, musculoskeletal disorders (MSDs) and the mental health status of 1675 coal miners in Xinjiang. METHODS: A cross-sectional investigation was carried out, and BDNF (rs6265, rs10835210) gene polymorphism and TPH2(rs4570625, rs4131347) gene polymorphism were identified in 30% of the study's participants. This study aimed to analyze the relationship between mental disorders, occupational stress and MSDs, and to explore the role of gene-gene and gene-environment interactions in respect to the incidence of psychological disorders. On this basis, the risk prediction model of mental disorders was constructed. RESULTS: The study identified the following risk factors for mental disorders among coal miners: Female, age, four shifts, coal miners, college education or above, single, occupational stress, and MSDs. MSDs, BDNF gene (rs6265) and TPH2 gene (rs4570625) are directly related to mental disorders, and interactions were found between MSDs and BDNF gene (rs6265),TPH2 gene (rs4570625), affecting the incidence of mental disorders. The Bayesian network model of mental disorders showed that MSDs, educational level, TPH2 gene (rs4570625) and marital status had a higher influence on mental disorders. Monthly income and educational level can indirectly affect mental disorders through occupational stress. BDNF gene (rs6265) and TPH2 gene (rs4570625) can indirectly affect mental disorders through MSDs. There may be an interaction between MSDs and educational level. CONCLUSIONS: Besides demographic characteristics, occupational stress and musculoskeletal disorders are also factors affecting the mental health of coal miners. It was found that BDNF rs10835210, TPH2 rs4570625 and TPH2 rs4131347 interact with each other, increasing the risk of mental disorders among coal miners.

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.

CYP3A Polymorphism and Chronic Mercury Intoxication.

We analyzed the relationship between polymorphic loci of CYP3A genes (CYP3A4 (rs2740574), CYP3A5 (rs776746) and CYP3A7 (rs2257401)) with the development of chronic mercury intoxication. Of 170 men examined, 120 were workers chronically exposed to mercury vapors and 50 were carriers of GG-HSPA1B (+1267A/G) genotype associated with chronic mercury intoxication. Urinary content of 4-hydroxyantipyrine (4-HAP) generated in the reaction predominantly catalyzed by CYP3A4/CYP3A5 was studied in workers without chronic mercury intoxication (group 1, N=46) and patients in the delayed period of chronic mercury intoxication (group 2, N=74) depending on the genotypes of CYP3A4 and CYP3A5. For polymorphic loci CYP3A5 and CYP3A7, a tendency to an increase in the frequency of genotypes with rare alleles was found (p=0.071 and p=0.078) in the combined group (group 2 together with GGHSPA1B genotype carriers) relative to group 1. The high level of linkage disequilibrium was noted, especially for the pair rs776746 and rs2257401 (LD (r)=0.89). In group 2, a trend to 4-HAP decrease compared to group 1 (p=0.056 and p=0.065) was revealed for carriers of AA-CYP3A4 and GG-CYP3A5 genotypes. The involvement of CYP3A in the development of mercury neurotoxic effect remains unclear.

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.

Polymorphism in GRHL2 gene may contribute to noise-induced hearing loss susceptibility: a meta-analysis.

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.

Noise induced epigenetic effects: A systematic review.

BACKGROUND: Noise-induced hearing loss (NIHL) is one of the leading causes of acquired sensorineural hearing loss. However, molecular mechanisms responsible for its pathogenesis remain to be elucidated. Epigenetic changes, i.e. DNA methylation, histone and microRNA expression modifications may function as a link between noise exposure and hearing loss. Therefore, the aim of the present review was to assess whether epigenetic alterations may serve as biomarkers of noise exposure or early effect. MATERIALS AND METHODS: A systematic review of studies available in Pubmed, Scopus, and ISI Web of Science databases was performed. RESULTS: Noise exposure was able to induce alterations in DNA methylation levels in workers and animal models, resulting in expression changes of genes related to hearing loss and also to extra-auditory effects. Differently expressed microRNAs were determined in NIHL workers compared to noise-exposed subjects with normal hearing, supporting their possible role as biomarkers of effect. Acoustic trauma affected histon acethylation and methylation levels in animals, suggesting their influence in the pathogenesis of acute noise-induced damage and their role as targets for potential therapeutic treatments. CONCLUSIONS: Although preliminary data suggest a relationship between noise and epigenetic effects, the limited number of studies, their different methodologies and the lack of adequate characterization of acoustic insults prevent definite conclusions. In this context, further research aimed to define the epigenetic impact of workplace noise exposure and the role of such alterations in predicting hearing loss may be important for the adoption of correct risk assessment and management strategies in occupational settings.

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.