Dataset Information

Chronic arsenic exposure suppresses ATM pathway activation in human keratinocytes.

ABSTRACT: An estimated 220 million people worldwide are chronically exposed to inorganic arsenic (iAs) primarily as a result of drinking iAs-contaminated water. Chronic iAs exposure is associated with a plethora of human diseases including skin lesions and multi-organ cancers. iAs is a known clastogen, inducing DNA double strand breaks (DSBs) in both exposed human populations and in vitro. However, iAs does not directly interact with DNA, suggesting that other mechanisms, such as inhibition of DNA repair and DNA Damage Response (DDR) signaling, may be responsible for iAs-induced clastogenesis. Recent RNA-sequencing data from human keratinocytes (HaCaT cells) indicate that mRNAs for phosphatases important for resolution of DDR signaling are induced as a result of chronic iAs exposure prior to epithelial to mesenchymal transition. Here, we report that phosphorylation of ataxia telengectasia mutated (ATM) protein at a critical site (pSer1981) important for DDR signaling, and downstream CHEK2 activation, are significantly reduced in two human keratinocyte lines as a result of chronic iAs exposure. Moreover, RAD50 expression is reduced in both of these lines, suggesting that suppression of the MRE11-RAD50-NBS1 (MRN) complex may be responsible for reduced ATM activation. Lastly, we demonstrate that DNA double strand break accumulation and DNA damage is significantly higher in human keratinocytes with low dose iAs exposure. Thus, inhibition of the MRN complex in iAs-exposed cells may be responsible for reduced ATM activation and reduced DSB repair by homologous recombination (HR). As a result, cells may favor error-prone DSB repair pathways to fix damaged DNA, predisposing them to chromosomal instability (CIN) and eventual carcinogenesis often seen resulting from chronic iAs exposure.

SUBMITTER: Nail AN

PROVIDER: S-EPMC9318262 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Chronic arsenic exposure suppresses ATM pathway activation in human keratinocytes.

Nail Alexandra N AN McCaffrey Lakynkalina M LM Banerjee Mayukh M Ferragut Cardoso Ana P AP States J Christopher JC

Toxicology and applied pharmacology 20220502

An estimated 220 million people worldwide are chronically exposed to inorganic arsenic (iAs) primarily as a result of drinking iAs-contaminated water. Chronic iAs exposure is associated with a plethora of human diseases including skin lesions and multi-organ cancers. iAs is a known clastogen, inducing DNA double strand breaks (DSBs) in both exposed human populations and in vitro. However, iAs does not directly interact with DNA, suggesting that other mechanisms, such as inhibition of DNA repair ...[more]

PMID: 35513056

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Project description:Chronic inorganic arsenic (iAs) exposure in drinking water is a global issue affecting >225 million people. Skin is a major target organ for iAs. miRNA dysregulation and chromosomal instability (CIN) are proposed mechanisms of iAs-induced carcinogenesis. CIN is a cancer hallmark and tetraploid cells can better tolerate increase in chromosome number and aberration, contributing to the evolution of CIN. miR-186 is overexpressed in iAs-induced squamous cell carcinoma relative to iAs-induced hyperkeratosis. Bioinformatic analysis indicated that miR-186 targets mRNAs of important cell cycle regulators including mitotic checkpoint serine/threonine kinase B (BUB1) and cell division cycle 27 (CDC27). We hypothesized that miR-186 overexpression contributes to iAs-induced transformation of keratinocytes by targeting mitotic regulators leading to induction of CIN. Ker-CT cells, a near diploid human keratinocyte cell line, were transduced with miR-186 overexpressing or scrambled control lentivirus. Stable clones were isolated after puromycin selection. Clones transduced with lentivirus expressing either a scrambled control miRNA or miR-186 were maintained with 0 or 100 nM iAs for 4 weeks. Unexposed scrambled control clones were considered as passage matched controls. Chronic iAs exposure increased miR-186 expression in miR-186 clones. miR-186 overexpression significantly reduced CDC27 levels irrespective of iAs exposure. The percentage of tetraploid or aneuploid cells was increased in iAs exposed miR-186 clones. Aneuploidy can arise from a tetraploid intermediate. Suppression of CDC27 by miR-186 may lead to impairment of mitotic checkpoint complex formation and its ability to maintain cell cycle arrest leading to chromosome misalignment. As a result, cells overexpressing miR-186 and chronically exposed to iAs may have incorrect chromosome segregation and CIN. These data suggest that dysregulation of miRNA by iAs mediates tetraploidy, aneuploidy and chromosomal instability contributing to iAs-induced carcinogenesis.

Project description:Following an official request to EFSA from the European Commission, EFSA assessed the chronic dietary exposure to inorganic arsenic (iAs) in the European population. A total of 13,608 analytical results on iAs were considered in the current assessment (7,623 corresponding to drinking water and 5,985 to different types of food). Samples were collected across Europe between 2013 and 2018. The highest mean dietary exposure estimates at the lower bound (LB) were in toddlers (0.30 μg/kg body weight (bw) per day), and in both infants and toddlers (0.61 μg/kg bw per day) at the upper bound (UB). At the 95th percentile, the highest exposure estimates (LB-UB) were 0.58 and 1.20 μg/kg bw per day in toddlers and infants, respectively. In general, UB estimates were two to three times higher than LB estimates. The mean dietary exposure estimates (LB) were overall below the range of benchmark dose lower confidence limit (BMDL 01) values of 0.3-8 μg/kg bw per day established by the EFSA Panel on Contaminants in the Food Chain in 2009. However, for the 95th percentile dietary exposure (LB), the maximum estimates for infants, toddlers and other children were within this range of BMDL 01 values. Across the different age classes, the main contributors to the dietary exposure to iAs (LB) were 'Rice', 'Rice-based products', 'Grains and grain-based products (no rice)' and 'Drinking water'. Different ad hoc exposure scenarios (e.g. consumption of rice-based formulae) showed dietary exposure estimates in average and for high consumers close to or within the range of BMDL 01 values. The main uncertainties associated with the dietary exposure estimations refer to the impact of using the substitution method to treat the left-censored data (LB-UB differences), to the lack of information (consumption and occurrence) on some iAs-containing ingredients in specific food groups, and to the effect of food preparation on the iAs levels. Recommendations were addressed to improve future dietary exposure assessments to iAs.

Dataset Information

Chronic arsenic exposure suppresses ATM pathway activation in human keratinocytes.

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Chronic arsenic exposure suppresses ATM pathway activation in human keratinocytes.

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