Commensal-related changes in the epidermal barrier function lead to alterations in the benzo[a]pyrene metabolite profile and its distribution in 3D-skin

ABSTRACT: Exposure to xenobiotics has repeatedly been associated with adverse health effects. While the majority of reported cases still relates to direct substance effects, there is increasing evidence that microbiome-dependent metabolism of xenobiotic substances likewise has direct adverse effects on the host. This can be due to microbial biotransformation of compounds, interaction between the microbiota and the host’s endogenous detoxification enzymes or altered xenobiotic bioavailability. Polycyclic aromatic hydrocarbons (PAH) such as Benzo[a]pyrene (B[a]P) are among the most abundant environmental pollutants and contaminants. Yet, effects of the skin microbiota on B[a]P absorption, metabolism and distribution in humans remain unclear. Here, we demonstrate that skin microbiota do metabolize B[a]P on and in human skin in situ, using a recently developed commensalic skin model. In this model microbial metabolism leads to high concentrations, of known microbial B[a]P metabolites on the surface as well as in the epidermal layers. In contrast to what was observed for uncolonized skin, metabolite as well as B[a]P concentrations were subject to altered rates of skin penetration and diffusion, resulting in up to 58 % reduction of metabolites recovered from basal culture medium. The results indicate the reason for this altered behavior to be a microbial induced change of the epidermal barrier function. Compared to uncolonized models, commensal colonization led to strengthening of tight junctions (TJ) as well as increased epidermal differentiation in the form of increased expression of E-cadherin, K10, FLG and IVN. Concomitantly colonized models showed decreased formation and penetration of the ultimate carcinogen Benzo[a]pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE), leading, in consequence, to fewer BPDE-DNA adducts formed. Befittingly, transcript and expression levels of key proteins for repairing environmentally induced DNA-damage such as XPC were also found to be reduced in the commensalic models, as was expression of B[a]P-associated cytochrome P450-dependent monooxygenases (CYPs) such as CYP1A1. The results show that the microbiome can have significant effects on the toxicology of external chemical impacts. The respective effects rely on a complex interplay between microbial as well as host metabolism and microbe-host interactions all of which cannot be adequately assessed using single-system studies. Given the high species-specificity of such interactions adequate toxicological assessments should thus increasingly rely on complex human models wherever possible.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171720 | GEO | 2021/09/13

REPOSITORIES: GEO