Polymorphisms in CLAUDIN1 and SPINK5 Influence Skin Absorption of Pyrene, Pyrimethanil, and Oxybenzone in Human Volunteers

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Absorption of chemicals through the skin affects occupational and environmental exposure to diverse compounds. We previously showed that loss-of-function (null) mutations and low-copy number variants (CNV) of Filaggrin (FLG), which encodes a key skin barrier protein, increased dermal chemical absorption; however, the FLG genotype did not explain all the observed variation. Here, we explore the effects of variation in genes encoding skin proteins that could affect chemical uptake. In a dermal exposure test, 23 null-FLG and 31 wild-type carriers were exposed to three common organic compounds: the polycyclic aromatic hydrocarbon pyrene, the fungicide pyrimethanil, and the ultraviolet-light absorber oxybenzone. Liquid chromatography-mass spectrometry was used to measure the concentrations of these chemicals or their metabolites in the subjects' urine collected over a 40-h period following exposure. We genotyped the participants for 14 polymorphisms in seven skin function-related genes (Filaggrin 2 [FLG2], including a new method for assessing FLG2 CNV, claudin 1 [CLDN1], serine peptidase inhibitor kazal type 5 [SPINK5], S100 calcium binding protein A7 [S100A7], transmembrane protein 79 [TMEM79], laminin subunit alpha 3 [LAMA3], and involucrin [IVL]) and performed a population toxicokinetic analysis. While controlling for FLG genotype, the CLDN1 rs893051 minor allele was associated with increased absorption, faster absorption rate, and longer lag time, while the SPINK5 rs2303067 minor allele was associated with shorter lag time. However, the differences in total systemic absorption were minor compared with FLG variants. Thus, FLG remains the predominant genetic determinant of chemical uptake through the skin.

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