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.

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.

Accumulation of inorganic arsenic (iAs) and dimethylarsenate (DMA) in rice threatens human health and rice yield, respectively. We studied the yet unclear interactions of soil sulfate amendment and water management for decreasing As accumulation in rice grain in a pot experiment. We show that soil sulfate amendment (+200 mg S/kg soil) decreased grain iAs by 44% without clearly increasing grain DMA under intermittent flooding from booting stage to maturation. Under continuous flooding during this period, sulfate amendment decreased grain iAs only by 25% but increased grain DMA by 68%. The mechanisms of sulfate amendment effects on grain iAs were not explained by porewater composition or in-planta As sequestration but were allocated to the rhizosphere. Grain iAs closely correlated with As in the root iron-plaque (r = 0.92) which was effectively decreased by sulfate amendment and may have acted as an iAs source for rice uptake. Although both sulfate amendment and intermittent flooding substantially increased porewater DMA concentrations, it was the continuous flooding, irrespective of sulfate amendment, that resulted in rice straighthead disease with 47-55% less yield and 258-320% more DMA in grains than intermittent flooding. This study suggests that combining soil sulfate amendment and intermittent flooding can help to secure the quantity and quality of rice produced in As-affected areas. Our results also imply the key role of rhizosphere processes in controlling both iAs and DMA accumulation in rice which should be elucidated in the future.

The booting stage and filling stage have been considered as the key stages for arsenic (As) uptake in rice. In this study, a field study was conducted to investigate the influence of the topdressing different amounts of silicon (Si) fertilizer at the key stages on rice As uptake and accumulation. The results showed that topdressing of a low amount of Si fertilizer at the booting stage and filling stage could increase rice yield, promote the formation of iron plaque and the retention of As on iron plaque, and reduce inorganic As content in brown rice. Compared with the control, the rice grain yield was increased by 22.60% with the topdressing of 20 kg·hm-2 Si fertilizer at the grain filling stage. As compared with the control, the Fe and As content in iron plaque under the topdressing of 20 kg·hm-2 Si fertilizer at the booting stage and filling stage was significantly (p < 0.05) increased by 84.34% and 87.78% (Fe content) and 70.96% and 63.80% (As content), respectively. Meanwhile, contents of As in rice roots, stems, and husks at the topdressing of 20 kg·hm-2 Si fertilizer at the booting stage were significantly (p < 0.05) reduced by 45.10%, 33.34%, and 31.23%, respectively, relative to the control. The lowest inorganic As content (0.21 mg·kg-1) in brown rice was obtained at the topdressing of 20 kg·hm-2 Si fertilizer at the booting stage, which was close to the National Food Limit Standard of 0.20 mg·kg-1 (GB 2762-2017). Therefore, topdressing of 20 kg·hm-2 Si fertilizer at the booting stage might be considered as an effective method to reduce inorganic As content in brown rice.

Rice consumption is a major dietary source of human exposure to arsenic (As), with As bioavailability being an important factor influencing its health risk. In this study, the As bioaccessibility was measured in 11 rice grains (140-335 μg As kg-1), which were compared to As relative bioavailability previously measured based on a mouse bioassay (Li et al., 2017). Using modified physiologically-based extraction test for rice (MPBET), As bioaccessibility in raw rice samples (44-88% in the gastric phase and 47-102% in the intestinal phase) was similar to those in cooked rice (42-73% and 43-99%). Arsenic bioaccessibility in rice was generally higher in the intestinal phase than in the gastric phase, with Fe and Ca concentrations in rice being negatively correlated with As bioaccessibility in the gastric phase (R2 = 0.47-0.49). In addition, for cooked rice, strong positive correlation was observed between bioaccessible As and inorganic As (R2 = 0.63-0.72), suggesting inorganic As in rice was easier to dissolve than organic As in gastrointestinal digestive fluids. Due to limited variation in As bioaccessibility and As bioavailability among the 11 samples, a weak correlation was observed between them (R2 = 0.01-0.03); however, As bioaccessibility values measured by the gastric phase (GP) of the MPBET agreed with As bioavailability values based on a mouse bioassay, suggesting the potential of the MPBETGP to predict As bioavailability in rice. Future work is needed to ascertain the robustness of the MPBETGP in predicting As bioavailability in rice using additional samples.

Arsenic (As) accumulation in rice grain is a significant public health concern. Inorganic As (iAs) is of particular concern because it has increased toxicity as compared to organic As. Irrigation management practices, such as alternate wetting and drying (AWD), as well as genotypic differences between cultivars, have been shown to influence As accumulation in rice grain. A 2 year field study using a Lemont × TeQing backcross introgression line (TIL) mapping population examined the impact of genotype and AWD severity on iAs grain concentrations. The \"Safe\"-AWD [35-40% soil volumetric water content (VWC)] treatment did not reduce grain iAs levels, whereas the more severe AWD30 (25-30% VWC) consistently reduced iAs concentrations across all genotypes. The TILs displayed a range of iAs concentrations by genotype, from less than 10 to up to 46 μg kg-1 under AWD30 and from 28 to 104 μg kg-1 under Safe-AWD. TIL grain iAs concentrations for flood treatments across both years ranged from 26 to 127 μg kg-1. Additionally, seven quantitative trait loci (QTLs) were identified in the mapping population associated with grain iAs. A subset of eight TILs and their parents were grown to confirm field-identified grain iAs QTLs in a controlled greenhouse environment. Greenhouse results confirmed the genotypic grain iAs patterns observed in the field; however, iAs concentrations were higher under greenhouse conditions as compared to the field. In the greenhouse, the number of days under AWD was negatively correlated with grain iAs concentrations. Thus, longer drying periods to meet the same soil VWC resulted in lower grain iAs levels. Both the number and combinations of iAs-affecting QTLs significantly impacted grain iAs concentrations. Therefore, identifying more grain iAs-affecting QTLs could be important to inform future breeding efforts for low iAs rice varieties. Our study suggests that coupling AWD practices targeting a soil VWC of less than or equal to 30% coupled with the use of cultivars developed to possess multiple QTLs that negatively regulate grain iAs concentrations will be helpful in mitigating exposure of iAs from rice consumption.