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DNA methylation of the cancer-related genes F2RL3 and AHRR is associated with occupational exposure to polycyclic aromatic hydrocarbons.

ABSTRACT: Some polycyclic aromatic hydrocarbons (PAH) are known carcinogens and workplace PAH exposure may increase the risk of cancer. Monitoring early cancer-related changes can indicate whether the exposure is carcinogenic. Here, we enrolled 151 chimney sweeps, 152 controls and 19 creosote-exposed male workers from Sweden. We measured urinary PAH metabolites using LC/MS/MS, the cancer-related markers telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) using qPCR, and DNA methylation of lung cancer-related genes F2RL3 and AHRR using pyrosequencing. The median 1-hydroxypyrene (PAH metabolite) concentrations were highest in creosote-exposed workers (8.0 μg/g creatinine) followed by chimney sweeps (0.34 μg/g creatinine) and controls (0.05 μg/g creatinine). TL and mtDNAcn did not differ between study groups. Chimney sweeps and creosote-exposed workers had significantly lower methylation of AHRR CpG site cg05575921 (88.1 and 84.9%, respectively) than controls (90%). Creosote-exposed workers (73.3%), but not chimney sweeps (76.6%) had lower methylation of F2RL3 cg03636183 than controls (76.7%). Linear regression analyses showed that chimney sweeps had lower AHRR cg05575921 methylation (B = -2.04; P < 0.057, adjusted for smoking and age) and lower average AHRR methylation (B = -2.05; P < 0.035), and non-smoking chimney sweeps had lower average F2RL3 methylation (B = -0.81; P < 0.042, adjusted for age) compared with controls. These cancer-related markers were not associated with urinary concentrations of PAH metabolites. In conclusion, although we found no associations with PAH metabolites in urine (short-term exposure), our results suggest dose-response relationship between PAH exposure and DNA hypomethylation of lung cancer-related loci. These findings indicate that further protective measures should be taken to reduce PAH exposure.

SUBMITTER: Alhamdow A

PROVIDER: S-EPMC6030939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAging is related to an increased risk of morbidity and mortality and is affected by environmental factors. Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health outcomes; but the association of such exposure with DNA methylation aging, a novel aging marker, is unclear.ObjectivesOur aim was to investigate the association of PAH exposure with methylation aging.MethodsWe trained and validated a methylation age predictor suitable for Chinese populations using whole blood methylation data in 989 Chinese and 160 Caucasians. We defined two aging indicators: δage, as methylation age minus chronological age; and aging rate, the ratio of methylation to chronological age. The association of PAH exposure with aging indicators was evaluated using linear regressions in three panels of healthy Chinese participants (N=539, among the aforementioned 989 Chinese participants) whose exposure levels were assessed by 10 urinary monohydroxy-PAH metabolites.ResultsWe developed a methylation age predictor providing accurate predictions in both Chinese individuals and Caucasian persons (R=0.94-0.96, RMSE=3.8-4.3). Among the 10 urinary metabolites that we measured, 1-hydroxypyrene and 9-hydroxyphenanthrene were associated with methylation aging independently of other OH-PAHs and risk factors; 1-unit increase in 1-hydroxypyrene was associated with a 0.53-y increase in Δage [95% confidence interval (CI): 0.18, 0.88; false discovery rate (FDR) FDR=0.004] and 1.17% increase in aging rate (95% CI: 0.36, 1.98; FDR=0.02), whereas for 9-hydroxyphenanthrene, the increase was 0.54-y for Δage (95% CI: 0.17, 0.91; FDR=0.004), and 1.15% for aging rate (95% CI: 0.31, 1.99; FDR=0.02). The association direction was consistent across the three Chinese panels with the association magnitude correlating with the panels' exposure levels; the association was validated by methylation data of purified leukocytes. Several cytosine-phosphoguanines, including those located on FHL2 and ELOVL2, were found associated with both aging indicators and monohydroxy-PAH levels.ConclusionsWe developed a methylation age predictor specific for Chinese populations but also accurate for Caucasian populations. Our findings suggest that exposure to PAHs may be associated with an adverse impact on human aging and epigenetic alterations in Chinese populations. https://doi.org/10.1289/EHP2773.

Project description:IntroductionWhen it is not possible to capture direct measures of occupational exposure or conduct biomonitoring, retrospective exposure assessment methods are often used. Among the common retrospective assessment methods, assigning exposure estimates by multiple expert rater review of detailed job descriptions is typically the most valid, but also the most time-consuming and expensive. Development of screening protocols to prioritize a subset of jobs for expert rater review can reduce the exposure assessment cost and time requirement, but there is often little data with which to evaluate different screening approaches. We used existing job-by-job exposure assessment data (assigned by consensus between multiple expert raters) from a large, population-based study of women to create and test screening algorithms for polycyclic aromatic hydrocarbons (PAHs) that would be suitable for use in other population-based studies.MethodsWe evaluated three approaches to creating a screening algorithm: a machine-learning algorithm, a set of a priori decision rules created by experts based on features (such as keywords) found in the job description, and a hybrid algorithm incorporating both sets of criteria. All coded jobs held by mothers of infants participating in National Birth Defects Prevention Study (NBDPS) (n = 35,424) were used in developing or testing the screening algorithms. The job narrative fields considered for all approaches included job title, type of product made by the company, main activities or duties, and chemicals or substances handled. Each screening approach was evaluated against the consensus rating of two or more expert raters.ResultsThe machine-learning algorithm considered over 30,000 keywords and industry/occupation codes (separate and in combination). Overall, the hybrid method had a similar sensitivity (87.1%) as the expert decision rules (85.5%) but was higher than the machine-learning algorithm (67.7%). Specificity was best in the machine-learning algorithm (98.1%), compared to the expert decision rules (89.2%) and hybrid approach (89.1%). Using different probability cutoffs in the hybrid approach resulted in improvements in sensitivity (24-30%), without the loss of much specificity (7-18%).ConclusionBoth expert decision rules and the machine-learning algorithm performed reasonably well in identifying the majority of jobs with potential exposure to PAHs. The hybrid screening approach demonstrated that by reviewing approximately 20% of the total jobs, it could identify 87% of all jobs exposed to PAHs; sensitivity could be further increased, albeit with a decrease in specificity, by adjusting the algorithm. The resulting screening algorithm could be applied to other population-based studies of women. The process of developing the algorithm also provides a useful illustration of the strengths and potential pitfalls of these approaches to developing exposure assessment algorithms.

Project description:BackgroundAlthough there is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) is linked with congenital heart defects (CHDs), few studies have examined the association in humans. We conducted a case-control study to examine the association between maternal exposure to PAHs and CHDs in offspring using data from the National Birth Defects Prevention Study (NBDPS) (1997-2011).MethodsWe obtained detailed information on maternal occupation during the month before to three months after conception. Expert raters, masked to case-control status, assessed job descriptions to assign categorical levels of exposure. Categories were quantitatively mapped to estimate cumulative exposure to PAHs, incorporating exposure intensity, frequency, work duration, and work hours. Quartiles were generated for cumulative maternal exposure to PAHs. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression for quartiles of PAH exposure and six CHD groupings (e.g. conotruncal) and specific subtypes (e.g. tetralogy of Fallot [ToF]). Final models were adjusted for maternal age, race/ethnicity, education, smoking, anticonvulsant use, folic acid supplementation, and study center.ResultsThere were 4,775 case and 7,734 control infants eligible for the study. The prevalence of occupational exposure to PAHs was 10.2% among both case and control mothers. In adjusted analysis, compared to mothers with no occupational PAH exposure, those in the highest quartile of exposure were more likely to have offspring in the conotruncal heart defects group (OR 1.41; 95% CI 1.00-2.00), and with ToF (OR 1.83; 95% CI 1.21-2.78).ConclusionsWomen in the highest quartile of estimated cumulative occupational PAH exposure during early pregnancy were more likely to have offspring with conotruncal heart defects, specifically ToF, compared to women with no occupational PAH exposure. Other comparisons between PAHs and other CHDs subgroups did not show any statistically precise associations.

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DNA methylation of the cancer-related genes F2RL3 and AHRR is associated with occupational exposure to polycyclic aromatic hydrocarbons.

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