Occupational exposure to polycyclic aromatic hydrocarbons and early biomarkers related to cardiovascular disease and cancer [Elektronisk resurs]

Polycyclic aromatic hydrocarbons (PAH) are omnipresent environmental pollutants composed of fused benzene rings and mainly produced by incomplete combustion of organic material. PAH exposure has been associated with increased risk of cancer and probably cardiovascular disease (CVD). In one way or another, everyone is exposed to PAH, but the dose and the period of exposure vary between individuals. Workers who remove soot from chimneys (chimney sweeps) are likely exposed to higher levels of PAH compared with the general population. However, whether the current PAH exposure among chimney sweeps leads to disease is not known. The overall aim of this thesis was to evaluate PAH exposure among currently working chimney sweeps as well as explore early biomarkers related to cardiovascular disease (CVD) and cancer. For this purpose, we recruited 151 chimney sweeps and 152 unexposed control individuals, all males from southern Sweden, from whom we collected questionnaires and biological samples. In one of the studies, we additionally used data and biological samples from 19 creosote-exposed workers, i.e. workers who impregnate wood panels with black oily material rich in PAH known as creosote. We found that PAH exposure (measured as PAH metabolites in urine) was up to 7 times higher among chimney sweeps compared with unexposed control workers, and the levels of PAH metabolites were positively associated with diastolic blood pressure. Moreover, we found higher serum concentrations of the classical risk markers for CVD (homocysteine and cholesterol) in chimney sweeps, compared with controls. Further, we found 25 putative CVD-related serum proteins differentially expressed between nonsmoking chimney sweeps and controls, among which follistatin (FS), heat shock protein beta-1 (HSP 27), and pro-interleukin-16 (IL-16) showed positive dose-response relationships with PAH metabolites. Pathway analysis demonstrated that these 25 proteins were mainly involved in inflammatory response and immune function. We also demonstrated hypomethylation (lower methylation) of the genes F2RL3 and AHRR, risk markers for lung cancer, among chimney sweeps and creosote-exposed workers, compared with controls. Notably, creosote-exposed workers had the highest PAH exposure and the lowest DNA methylation, compared with both chimney sweeps and controls, which suggests a dose-response relationship. In addition, we found 17 putative cancer-related serum proteins differentially expressed between nonsmoking chimney sweeps and controls, among which kallikrein-13 (KLK13) showed positive dose-response relationships with the metabolites of carcinogenic PAH (BaP and BaA). Pathway analysis showed that most of the differentially expressed proteins were involved in cell movement, cell migration, and cell invasion. Overall, findings from this thesis indicate that (i) currently working chimney sweeps are markedly exposed to PAH, (ii) chimney sweeps showed molecular changes related to CVD and cancer, and (iii) some of these molecular changes seem to be, at least partly, induced by PAH exposure. These results stress that protective measures are warranted to reduce PAH exposure among chimney sweeps as well as other occupational groups at risk of PAH exposure. In addition, further research exploring mechanisms of PAH-induced CVD and cancer is encouraged in order to develop strategies of early detection of disease among individuals known to be exposed to PAH

Filaggrin variations are associated with PAH metabolites in urine and DNA alterations in blood

Dermal chemical exposure is common in many professions. The filaggrin protein is important for the skin barrier and variations in the filaggrin gene (FLG) may influence the uptake of chemicals via the skin, and consequently, the degree of systemic effects. The aim of this study was to investigate, in chimney sweeps with occupational exposure to polycyclic aromatic hydrocarbons (PAH) from soot, the influence of variation in FLG on internal PAH dose and DNA alterations, including epigenetic, previously linked to cancer and cardiovascular disease. We used TaqMan PCR to genotype 151 chimney sweeps and 152 controls for four FLG null variants (R501X, R2447X, S3247X and 2282del4) which cause impaired skin barrier, and FLG copy number variation (12th repeat, CNV12) which potentially is beneficial for the skin barrier. The internal dose of PAH was represented by urinary PAH metabolites (e.g. 1-hydroxypyrene and 3-hydroxybenzo[a]pyrene) that we measured by LC-MS/MS. We measured epigenetic alterations (methylation of AHRR and F2RL3) in blood by pyrosequencing; and DNA alterations (telomere length and mitochondrial DNA copy number) by real-time PCR. Hypomethylation of AHRR or F2RL3 is a risk factor for lung cancer and shorter telomere length a risk factor for cardiovascular disease. The frequencies of FLG null were 8.6 and 11.8% (p = 0.35), and CNV12 27.8 and 19.7% (p = 0.09) in chimney sweeps and controls, respectively. We found that among chimney sweeps working predominately with soot sweeping (high PAH exposure), CNV12 carriers had lower concentrations of PAH metabolites in urine compared with non-carriers (median 1-hydroxypyrene = 0.37 vs 0.86 μg/g creatinine respectively; p = 0.025 by linear regression models adjusted for age, BMI and smoking) compared to sweeps not carrying CNV12. Further, FLG null was associated with approximately 2.5% higher methylation of F2RL3 (cg03636183, p = 0.019 after adjustment for exposure group, age, BMI and smoking). FLG null was associated with approximately 7% shorter telomere length (p = 0.015, adjusted model). Our results suggest that FLG variations may influence the dose of PAH in highly exposed workers, possibly via dermal uptake. It also suggests that FLG variation may influence the degree of (epi)genotoxicity in the body. FLG variation is common in the working population and should be considered in risk assessment

Polymorphisms in ATP-binding cassette transporters associated with maternal methylmercury disposition and infant neurodevelopment in mother-infant pairs in the Seychelles Child Development Study

BACKGROUND: ATP-binding cassette (ABC) transporters have been associated with methylmercury (MeHg) toxicity in experimental animal models. AIMS: To evaluate the association of single nucleotide polymorphisms (SNPs) in maternal ABC transporter genes with 1) maternal hair MeHg concentrations during pregnancy and 2) child neurodevelopmental outcomes. MATERIALS AND METHODS: Nutrition Cohort 2 (NC2) is an observational mother-child cohort recruited in the Republic of Seychelles from 2008-2011. Total mercury (Hg) was measured in maternal hair growing during pregnancy as a biomarker for prenatal MeHg exposure (N=1313) (mean 3.9ppm). Infants completed developmental assessments by Bayley Scales of Infant Development II (BSID-II) at 20months of age (N=1331). Genotyping for fifteen SNPs in ABCC1, ABCC2 and ABCB1 was performed for the mothers. RESULTS: Seven of fifteen ABC SNPs (ABCC1 rs11075290, rs212093, and rs215088; ABCC2 rs717620; ABCB1 rs10276499, rs1202169, and rs2032582) were associated with concentrations of maternal hair Hg (p<0.001 to 0.013). One SNP (ABCC1 rs11075290) was also significantly associated with neurodevelopment; children born to mothers with rs11075290 CC genotype (mean hair Hg 3.6ppm) scored on average 2 points lower on the Mental Development Index (MDI) and 3 points lower on the Psychomotor Development Index (PDI) than children born to mothers with TT genotype (mean hair Hg 4.7ppm) while children with the CT genotype (mean hair Hg 4.0ppm) had intermediate BSID scores. DISCUSSION: Genetic variation in ABC transporter genes was associated with maternal hair Hg concentrations. The implications for MeHg dose in the developing child and neurodevelopmental outcomes need to be further investigated