Toxicological Sciences
Toxicological Sciences
5 years ago

High susceptibility of Lrig1 sebaceous stem cells to TCDD in mice.

Sorg, Fontao, Barnes, Saurat, Kaya
We have previously shown that CYP1A1 was highly induced for a long period of time in a patient who had been poisoned by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound known to activate the aryl hydrocarbon receptor (AhR). During that period of time no sebaceous glands could be observed in the skin of this patient. In the present study, starting from observations in the patient exposed to TCDD, we analysed the seboatrophy induced by dioxins in mice. We observed a very different pattern of AhR and CYP1A1 immunostaining in skin biopsies of the patient. When applying TCDD and beta-naphthoflavone (BNF), another AhR agonist, on the ears of C57BL/6J mice, we reproduced (i) an atrophy of sebaceous glands, (ii) a strong induction of CYP1A1 within the glands, and (iii) a dramatic repression of the genes encoding the sebogenic enzymes AWAT1, ELOVL3 and SCD1. These effects were reversible. LRIG1 expressing progenitor cells, found in the vicinity of sebaceous glands, were shown to be the initial skin cellular targets of AhR agonists. These cells retained the DNA label BrdU and co-localised with the CYP1A1 protein for at least 30 days. A downregulation of LRIG1 by siRNA in cultured sebocytes significantly decreased the CYP1A1 response to TCDD, indicating that LRIG1 contributes to a higher susceptibility of AhR agonists. In conclusion these observations provide for the first time a strong experimental support to the concept that dioxin-induced skin pathology may be driven by a molecular switch in progenitor cells involved in the physiological turnover of sebaceous glands.

Publisher URL: http://doi.org/10.1093/toxsci/kfx179

DOI: 10.1093/toxsci/kfx179

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