Prenatal arsenic exposure alters keratinocyte stem cell fate through persistent activation of IGF2R-MAPK cascade leading to aggravated skin carcinogenesis in mice offspring.

Autor: Chauhan A; Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Gangopadhyay S; Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Sharma V; Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India., Singh S; Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Koshta K; Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Singh D; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.; Animal Facility, ASSIST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India., Ansari KM; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.; Food Toxicology Laboratory, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India., Srivastava V; Systems Toxicology Group, FEST Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
Jazyk: angličtina
Zdroj: Molecular carcinogenesis [Mol Carcinog] 2024 May; Vol. 63 (5), pp. 817-833. Date of Electronic Publication: 2024 Feb 01.
DOI: 10.1002/mc.23690
Abstrakt: Chronic exposure to arsenic (As) promotes skin carcinogenesis in humans and potentially disturbs resident stem cell dynamics, particularly during maternal and early life exposure. In the present study, we demonstrate how only prenatal arsenic exposure disturbs keratinocyte stem cell (KSC) conditioning using a BALB/c mice model. Prenatal As exposure alters the normal stemness (CD34, KRT5), differentiation (Involucrin), and proliferation (PCNA) program in skin of offspring with progression of age as observed at 2, 10, and 18 weeks. Primary KSCs isolated from exposed animal at Day-2 showed increased survival (Bax:Bcl-xL, TUNEL assay), proliferation (BrdU), and differentiation (KRT5, Involucrin) potential through the activation of pro-carcinogenic IGF2R-MAPK cascade (IGF2R-G(α)q-MEK1-ERK1/2). This was associated with reduced enrichment of histone H3K27me3 and its methylase, EZH2 along with increased binding of demethylase, KDM6A at Igf2r promoter. Altered KSCs conditioning through disturbed Igf2r imprint contributed to impaired proliferation and differentiation and an aggravated tumor response in offspring.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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