Uptake of Chemicals through the Skin: An Important Role of Filaggrin Gene Variants.

Environmental chemicals can enter the human body through oral consumption, inhalation, or skin absorption. The latter exposure route may have been underappreciated, according to Karin Broberg, a professor of environmental medicine at the Karolinska Institute and Lund University, Sweden. That is one reason she decided to study the genetic effects on skin permeability for selected chemicals. Broberg and her colleagues recently published the results of their research in Environmental Health Perspectives.1 They reported that common variants of the filaggrin-expressing gene, FLG, were associated with an increased uptake of chemicals through the skin of human volunteers.

The variants studied included the four most common “loss of function” (LOF) mutations in northern Europeans, mutations that prevent the proper assembly of filaggrin.2 The researchers also quantified copy number variants (CNVs), or nearly identical repeat sequences (high versus low), in one part of the FLG gene. CNVs may influence filaggrin function even in people who do not carry LOF mutations.3

Filament-aggregating protein—or filaggrin—plays an important role in the skin’s ability to maintain a strong barrier. Loss-of-function gene mutations can make carriers vulnerable to the transfer of allergens through the skin.4 The same may hold true for the transfer of environmental chemicals. Image: © zefart/Shutterstock.

Filaggrin is a large structural protein that contributes to the skin’s barrier role. Its smaller constituent amino acids act as skin softeners and moisturizers and regulate pH levels and water resistance.4 An effect of the FLG gene on dermal uptake of chemicals is supported by observational studies. For example, cross-sectional studies of Danish men have associated LOF mutations in FLG with higher urinary concentrations of phthalates5 and of phenols, parabens, and ultraviolet filters.6 A case–control study of Swedish chimney sweeps associated high CNVs with lower urinary levels of polycyclic aromatic hydrocarbons (PAHs) from soot.7

In the new study, 6.5% of 432 genotyped volunteers carried an LOF mutation and were invited to participate in the dermal exposure experiment, along with age-matched controls. The researchers collected preexposure blood and urine samples from 54 individuals (23 FLG mutation carriers, 31 “typical” wild-type carriers). Next, they applied solutions of three chemicals of interest to different areas of the volunteers’ arms. These chemicals were pyrene (a PAH formed by the combustion of organic material8,9), pyrimethanil (a fungicide commonly used in fruit farming10), and oxybenzone (an ultraviolet light absorber found in many sunscreen products11,12). After 4 hours of exposure, the participants again provided blood samples and were asked to collect all urine excreted for 48 hours.

Wild-type carriers were distinguished by whether they had low or high CNVs. Urinary biomarkers of the three chemicals were analyzed by liquid chromatography–mass spectrometry. The three genotype groups differed widely in the lag time between absorption of each chemical via the skin and excretion in urine. In both mutation and wild-type/low CNV carriers, the lag time was shorter than in wild-type/high CNV carriers.

“Our results show that FLG genotypes influence the levels of chemicals that [enter] our body,” says Broberg. “This example of gene–environment interaction requires validation in independent studies but suggests that low CNV carriers may be as susceptible as mutation carriers to a higher uptake.”

With up to 10% of European individuals carrying an FLG LOF mutation13 and 30% having low CNVs,3 this is a surprisingly powerful result, says Sara Brown, a professor of dermatology at the University of Edinburgh, United Kingdom, who was not involved in the study.

“This is a high-quality, carefully conducted study,” says Brown. The finding is especially compelling, she says, because not only LOF mutations but also the CNV appears to affect uptake of chemicals through the skin. She adds that important next steps include studying non-White ethnicities and testing whether other genes that control the skin’s also affect the penetration of chemicals.

Jacob Pontoppidan Thyssen, a professor of dermatology at the University of Copenhagen, Denmark, agrees with Brown on the high quality of the work, although he notes the lack of measured filaggrin levels in the skin. “Future risk assessment should take into account that individuals with genetically impaired skin barriers are more susceptible to the effects of environmental chemicals,” says Thyssen, who also was not involved in the research. “We should also study if and how FLG mutations affect the penetration of topical drugs.”

FLG mutations are powerful risk factors for atopic dermatitis3,14 and related systemic atopic diseases, such as asthma,15 hay fever,16 and food allergies.17 If this gene also modulates the uptake of environmental chemicals during years of exposure, its potentially even broader systemic effects deserve further study, says Brown. She concludes, “This new research provides convincing evidence that common differences in [skin barrier function] affect the absorption of chemicals that are all around us.”