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

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.

Arsenic (As) accumulation in different genotypes of indica rice (Oryza sativa L.) and health risk assessment based on inorganic As.

To reveal differences in arsenic (As) accumulation among indica rice cultivars and assess the human health risks arising from inorganic arsenic (iAs) intake via rice consumption, a total of 320 field indica rice samples and corresponding soil samples were collected from Fujian Province in China. The results showed that available soil As (0.03 to 3.83 mg/kg) showed a statistically significant positive correlation with total soil As (0.10 to 19.45 mg/kg). The inorganic As content in brown rice was between 0.001 and 0.316 mg/kg. Among the cultivars, ten brown rice samples (3.13%) exceeded the maximum contaminant level (MCL) of iAs in food of 0.2 mg/kg in China. The estimated daily intake (EDI) and calculated individual incremental lifetime cancer risk (ILCR) ranged from 0.337 µg/day to 106.60 µg/day and from 8.18 × 10-6 to 2.59 × 10-3, respectively. Surprisingly, the average EDI and the EDIs of 258 (80.63%) brown rice samples were higher than the maximum daily intake (MDI) of 10 µg/day in drinking water as set by the National Research Council. The mean ILCR associated with iAs was 54.3 per 100,000, which exceeds the acceptable upper limit (AUL) of 10 per 100,000 set by the USEPA. Notably, the cultivars Y-Liang-You 1 and Shi-Ji 137 exhibited significantly higher mean ILCRs compared to the AUL and other cultivars, indicating that they pose more serious cancer risks to the local population. Finally, this study demonstrated that the cultivars Yi-Xiang 2292 and Quan-Zhen 10 were the optimal cultivars to mitigate risks associated with iAs to human health from rice consumption.

Activated fibroblasts modify keratinocyte stem niche through TET1 and IL-6 to promote their rapid transformation in a mouse model of prenatal arsenic exposure.

Early life exposure to environmental pollutants such as arsenic (As) can increase the risk of cancers in the offspring. In an earlier study, we showed that only prenatal As exposure significantly increases epidermal stem cell proliferation and accelerates skin tumorigenesis in BALB/c mouse offspring. In the present work, we have examined the role of As-conditioned dermal fibroblasts (DFs) in creating pro-tumorigenic niches for Keratinocyte stem cells (KSCs) in the offspring. DFs isolated from prenatally exposed animals showed increased levels of activation markers (α-SMA, Fibronectin, Collagen IV), induction of ten-eleven translocation methylcytosine dioxygenase 1(TET1), and secreted high levels of niche modifying IL-6. This led to enhanced proliferation, migration, and survival of KSCs. Increased IL-6 production in As-conditioned fibroblast was driven through TET1 mediated 5-mC to 5-hmC conversion at -698/-526 and -856/-679 region on its promoter. IL-6 further acted through downstream activation of JAK2-STAT3 signaling, promoting epithelial-to-mesenchymal transition (EMT) in KSCs. Inhibition of pSTAT3 induced by IL-6 reduced the EMT process in KSCs resulting in a significant decrease in their proliferation, migration, and colony formation. Our results indicate that IL-6 produced by prenatally conditioned fibroblasts plays a major role in regulating the KSC niche and promoting skin tumor development in As-exposed offspring.