German Federal Institute for Risk Assessment, Department of Pesticides Safety, Berlin, Germany.
Institute of Pharmacy, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany.
mBio. 2021 Oct 26;12(5):e0122321. doi: 10.1128/mBio.01223-21. Epub 2021 Sep 28.
Polycyclic aromatic hydrocarbons (PAH) such as benzo[]pyrene (B[]P) are among the most abundant environmental pollutants, resulting in continuous exposure of human skin and its microbiota. However, effects of the latter on B[]P toxicity, absorption, metabolism, and distribution in humans remain unclear. Here, we demonstrate that the skin microbiota does metabolize B[]P on and in human skin , using a recently developed commensal skin model. In this model, microbial metabolism leads to high concentrations of known microbial B[]P metabolites on the surface as well as in the epidermal layers. In contrast to what was observed for uncolonized skin, B[]P and its metabolites 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 microbially induced strengthening of the epidermal barrier. Concomitantly, colonized models showed decreased formation and penetration of the ultimate carcinogen B[]P-7,8-dihydrodiol-9,10-epoxide (BPDE), leading, in consequence, to fewer BPDE-DNA adducts being formed. Befittingly, transcript and expression levels of key proteins for repairing environmentally induced DNA damage such as xeroderma pigmentosum complementation group C (XPC) were also found to be reduced in the commensal models, as was expression of B[]P-associated cytochrome P450-dependent monooxygenases (CYPs). 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 and host metabolism and microbe-host interactions, all of which cannot be adequately assessed using single-system studies. Exposure to xenobiotics has repeatedly been associated with adverse health effects. While the majority of reported cases relate 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. However, there are hardly any studies addressing the complex interplay of such interactions and less so in human test systems. Using a recently developed microbially competent three-dimensional (3D) skin model, we show here for the first time how commensal influence on skin physiology and gene transcription paradoxically modulates PAH toxicity.
多环芳烃（PAH），如苯并[a]芘（B[a]P），是最丰富的环境污染物之一，导致人体皮肤及其微生物群持续暴露。然而，后者对 B[a]P 毒性、吸收、代谢和分布在人体中的影响仍不清楚。在这里，我们证明了皮肤微生物群可以在人类皮肤上代谢 B[a]P，使用最近开发的共生皮肤模型。在这个模型中，微生物代谢导致表面以及表皮层中存在高浓度的已知微生物 B[a]P 代谢物。与未定植皮肤观察到的情况相反，B[a]P 及其代谢物的皮肤穿透和扩散速度发生变化，导致从基底培养基中回收的代谢物减少多达 58%。结果表明，这种行为改变的原因是微生物诱导的表皮屏障增强。同时，定植模型显示最终致癌剂 B[a]P-7,8-二氢二醇-9,10-环氧化物（BPDE）的形成和穿透减少，导致形成的 BPDE-DNA 加合物减少。相应地，修复环境诱导的 DNA 损伤的关键蛋白质的转录和表达水平，如着色性干皮病互补组 C（XPC），也在共生模型中降低，B[a]P 相关细胞色素 P450 依赖性单加氧酶（CYPs）的表达也降低。结果表明，微生物组可以对外部化学物质的毒理学产生重大影响。各自的影响依赖于微生物和宿主代谢以及微生物-宿主相互作用之间的复杂相互作用，而这些都不能通过单一系统研究来充分评估。 暴露于异源生物已多次与不良健康影响相关联。虽然大多数报道的病例都与直接物质作用有关，但越来越多的证据表明，异源生物物质的微生物依赖性代谢同样对宿主有直接的不良影响。这可能是由于化合物的微生物生物转化、微生物群与宿主内源性解毒酶之间的相互作用，或异源生物的生物利用度改变。然而，几乎没有研究涉及到这种相互作用的复杂相互作用，在人体测试系统中更是如此。使用最近开发的微生物相容的三维（3D）皮肤模型，我们在这里首次展示了共生如何影响皮肤生理学和基因转录，从而改变多环芳烃的毒性。
