Abstract

Background:

The filaggrin protein is important for skin barrier structure and function. Loss-of-function (null) mutations in the filaggrin gene FLG may increase dermal absorption of chemicals.

Objective:

The objective of the study was to clarify if dermal absorption of chemicals differs depending on FLG genotype.

Method:

We performed a quantitative real-time polymerase chain reaction (qPCR)-based genetic screen for loss-of-function mutations (FLG null) in 432 volunteers from the general population in southern Sweden and identified 28 FLG null carriers. In a dermal exposure experiment, we exposed 23 FLG null and 31 wild-type (wt) carriers to three organic compounds common in the environment: the polycyclic aromatic hydrocarbon pyrene, the pesticide pyrimethanil, and the ultraviolet-light absorber oxybenzone. We then used liquid-chromatography mass-spectrometry to measure the concentrations of these chemicals or their metabolites in the subjects’ urine over 48 h following exposure. Furthermore, we used long-range PCR to measure FLG repeat copy number variants (CNV), and we performed population toxicokinetic analysis.

Results:

Lag times for the uptake and dermal absorption rate of the chemicals differed significantly between FLG null and wt carriers with low (20–22 repeats) and high FLG CNV (23–24 repeats). We found a dose-dependent effect on chemical absorption with increasing lag times by increasing CNV for both pyrimethanil and pyrene, and decreasing area under the urinary excretion rate curve (${\text{AUC}}_{(0–40\mathrm{h})}$) with increasing CNV for pyrimethanil. FLG null carriers excreted 18% and 110% more metabolite (estimated by ${\text{AUC}}_{(0–40\mathrm{h})}$) for pyrimethanil than wt carriers with low and high CNV, respectively.

Conclusion:

We conclude that FLG genotype influences the dermal absorption of some common chemicals. Overall, FLG null carriers were the most susceptible, with the shortest lag time and highest rate constants for skin absorption, and higher fractions of the applied dose excreted. Furthermore, our results indicate that low FLG CNV resulted in increased dermal absorption of chemicals. https://doi.org/10.1289/EHP7310

中文翻译：

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聚丝蛋白多态性和化学物质通过皮肤的吸收——一项人体实验研究

摘要

背景：

丝聚蛋白对皮肤屏障结构和功能很重要。丝聚蛋白基因FLG中的功能丧失（无效）突变可能会增加化学物质的皮肤吸收。

客观的：

该研究的目的是澄清化学物质的皮肤吸收是否因FLG基因型而异。

方法：

我们对瑞典南部普通人群的 432 名志愿者进行了基于实时聚合酶链反应 (qPCR) 的功能丧失突变 ( FLG null) 的定量遗传筛查，并确定了 28 名FLG无效携带者。在皮肤暴露实验中，我们将 23 个FLG无效载体和 31 个野生型 (wt) 载体暴露于环境中常见的三种有机化合物：多环芳烃芘、农药嘧霉胺和紫外线吸收剂氧苯酮。然后，我们使用液相色谱质谱法测量暴露后 48 小时内受试者尿液中这些化学物质或其代谢物的浓度。此外，我们使用长距离 PCR 来测量FLG 重复拷贝数变异（CNV），我们进行了群体毒代动力学分析。

结果：

FLG null 和 wt 载体之间的化学物质吸收和皮肤吸收率的滞后时间显着不同，具有低（20-22 次重复）和高FLG CNV（23-24 次重复）。我们发现，通过增加嘧霉胺和芘的 CNV 和减少尿排泄率曲线下的面积，随着滞后时间的增加，对化学吸收的影响呈剂量依赖性。${\text{AUC}}_{(0——40\mathrm{H})}$) 随着嘧霉胺的 CNV 增加。FLG无效携带者排出的代谢物分别多出 18% 和 110%（估计${\text{AUC}}_{(0——40\mathrm{H})}$) 对于嘧霉胺，分别比具有低和高 CNV 的 wt 载体。

结论：

我们得出结论，FLG基因型会影响一些常见化学物质的皮肤吸收。总体而言，FLG无效载体是最敏感的，具有最短的延迟时间和最高的皮肤吸收速率常数，并且排泄的应用剂量比例更高。此外，我们的结果表明，低FLG CNV 会导致皮肤对化学品的吸收增加。https://doi.org/10.1289/EHP7310