Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Environ Res. 2019 Oct;177:108600. doi: 10.1016/j.envres.2019.108600. Epub 2019 Jul 22.
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.
皮肤接触化学物质在许多职业中很常见。丝聚合蛋白对于皮肤屏障很重要，丝聚合蛋白基因（FLG）的变异可能会影响化学物质通过皮肤的吸收，进而影响全身效应的程度。本研究旨在调查从事烟囱清扫工作的人群中，职业性暴露于煤烟中的多环芳烃（PAH）对内部 PAH 剂量和 DNA 改变（包括先前与癌症和心血管疾病相关的表观遗传改变）的影响。我们使用 TaqMan PCR 对 151 名烟囱清洁工和 152 名对照者进行 151 名烟囱清洁工和 152 名对照者进行 4 种 FLG 无功能突变（R501X、R2447X、S3247X 和 2282del4）和 FLG 拷贝数变异（第 12 个重复，CNV12）的基因分型，这些突变会导致皮肤屏障受损，而 CNV12 可能对皮肤屏障有益。我们通过液相色谱-串联质谱法（LC-MS/MS）测量尿液中 PAH 代谢物（如 1-羟基芘和 3-羟基苯并[a]芘）来表示 PAH 的内部剂量。我们通过焦磷酸测序测量血液中的表观遗传改变（AHRR 和 F2RL3 的甲基化）；并通过实时 PCR 测量 DNA 改变（端粒长度和线粒体 DNA 拷贝数）。AHRR 或 F2RL3 的低甲基化是肺癌的危险因素，端粒长度较短是心血管疾病的危险因素。在烟囱清洁工和对照组中，FLG 无功能的频率分别为 8.6%和 11.8%（p=0.35），CNV12 为 27.8%和 19.7%（p=0.09）。我们发现，在主要从事清扫烟尘工作的烟囱清洁工（高 PAH 暴露）中，与非携带者相比，CNV12 携带者尿液中的 PAH 代谢物浓度较低（中位数 1-羟基芘分别为 0.37 和 0.86μg/g 肌酐；p=0.025，经线性回归模型调整，包括年龄、BMI 和吸烟）。此外，FLG 无功能与 F2RL3 约 2.5%的高甲基化相关（cg03636183，p=0.019，经暴露组、年龄、BMI 和吸烟调整）。FLG 无功能与端粒长度缩短约 7%相关（p=0.015，调整模型）。我们的结果表明，FLG 变异可能通过皮肤吸收影响高暴露工人的 PAH 剂量，也可能影响体内的（表观遗传）遗传毒性程度。FLG 变异在工作人群中很常见，应在风险评估中考虑。
