Arsenic exposure alters the expression of genes related to metabolic diseases in differentiated adipocytes and in newborns and children.

The mechanisms underlying the association between prenatal arsenic exposure and the development of metabolic diseases remain unclear. Aberrant adipogenesis and adipokine production are associated with increased risk for the development of metabolic diseases in susceptible populations. Generation of mature adipocytes is tightly regulated by the expression of genes encoding: peroxisome proliferator-activated receptor γ (PPARG), fatty acid-binding protein (FABP4), and glucose transporter-4 (SLC2A4), and adipokines such as leptin (LEP) and adiponectin (ADIPOQ). This study aimed to investigate the expression of these genes, which are associated with the pathogenesis of metabolic diseases in newborns and children exposed to arsenic in utero. A high arsenic exposed group showed significantly decreased PPARG and FABP4 expression in cord blood samples from newborns and in saliva samples from children. By contrast, the expression of the SLC2A4 and ADIPOQ mRNA was significantly decreased in high-arsenic exposed children. Furthermore, the levels of toenail arsenic were negatively correlated with the salivary mRNA expression levels of PPARG (r = -0.412, p < 0.01), aP2 (r = -0.329, p < 0.05), and SLC2A4 (r = -0.528, p < 0.01). In vitro studies utilizing umbilical cord derived mesenchymal stem cells (UC-MSCs) as a surrogate for fetal MSCs showed that arsenite treatment (0.5 µM and 1 µM) significantly impaired adipogenic differentiation in a concentration dependent manner. Such impairment may be related to a significant decrease in the expression of: PPARγ, FABP4, and SLC2A4 observed at 1 µM arsenite. Arsenite treatment also promoted inflammation through a significant increase in the mRNA expression levels of the pro-inflammatory adipokine, LEP, and the inflammatory cytokines: CXCL6, IL-1ß, and CXCL8. Collectively, our results suggests that such alterations may be a consequence of the effects of arsenic exposure on fetal MSCs eventually leading to impaired adipogenic differentiation and the promotion of inflammation, both of which contribute to the development of metabolic diseases later in life.

In utero arsenic exposure increases DNA damage and gene expression changes in umbilical cord mesenchymal stem cells (UC-MSCs) from newborns as well as in UC-MSC differentiated hepatocytes.

Prenatal exposure to arsenic is associated with an increased risk of disease development such as liver cancer in adulthood. Increasing evidence suggests that fetal stem cells are key targets during transplacental chemical exposure. Our earlier study reported that in utero arsenic exposure caused various types of DNA damage in newborns. In this study, we further investigated the effects of prenatal arsenic exposure on mutagenic DNA damage in umbilical cord mesenchymal stem cells (MSCs) that represent fetal stem cells from the same birth cohort. DNA damage measured as 8-hydroxydeoxyguanine (8-OHdG) and 8-nitroguanine was increased in umbilical cord MSCs of newborns in relation to maternal arsenic levels in a dose-dependent manner. Levels of 8-OHdG and 8-nitroguanine were significantly (p < 0.05) and positively associated with arsenic levels in cord blood and maternal toenails. In vitro studies confirmed that arsenite treatment alone (0-5 µM, 24 h) significantly increased the levels of 8-OHdG and 8-nitroguanine in an MSC cell line derived from umbilical cord tissue (UC-MSCs). When UC-MSCs were allowed to differentiate into hepatocytes in the presence of arsenite (0.5 µM, 21 days), there were significant increases (p < 0.05) in 8-OHdG and 8-nitroguanine compared to those observed in undifferentiated UC-MSCs. Moreover, in these arsenite-exposed differentiated hepatocytes, expression of inflammatory genes (CXCL6 and CXCL8) and an oxidative stress response gene (NFE2L2) was increased, while that of a DNA repair gene (OGG1) was decreased. Arsenite treatment also increased cell transformation ability of hepatocytes differentiated from UC-MSCs. These results suggest that arsenic exposure increases mutagenic DNA damage in fetal stem cells which continued when these cells differentiated to become hepatocytes which have increased cell transformation ability. This study highlights the potential risk of in utero arsenic exposure, which may lead to liver disease and cancer development later in life.

Aerosol mass and size-resolved metal content in urban Bangkok, Thailand.

Inhalable particulate matter (PM) is a health concern, and people living in large cities such as Bangkok are exposed to high concentrations. This exposure has been linked to respiratory and cardiac diseases and cancers of the lung and brain. Throughout 2018, PM was measured in northern Bangkok near a toll road (13.87°N, 100.58°E) covering all three seasons (cool, hot and rainy). PM10 was measured in 24- and 72-h samples. On selected dates aerodynamic size and mass distribution were measured as 3-day samples from a fixed 5th floor inlet. Particle number concentration was measured from the 5th floor inlet and in roadside survey measurements. There was a large fraction of particle number concentration in the sub-micron range, which showed the greatest variability compared with larger fractions. Metals associated with combustion sources were most found on the smaller size fraction of particles, which may have implications for associated adverse health outcomes because of the likely location of aerosol deposition in the distal airways of the lung. PM10 samples varied between 30 and 100 µg m-3, with highest concentrations in the cool season. The largest metal fractions present in the PM10 measurements were calcium, iron and magnesium during the hot season with average airborne concentrations of 13.2, 3.6 and 2.0 µg m-3, respectively. Copper, zinc, arsenic, selenium, molybdenum, cadmium, antimony and lead had large non-crustal sources. Principal component analysis (PCA) identified likely sources of the metals as crustal minerals, tailpipe exhaust and non-combustion traffic. A health risk analysis showed a higher risk of both carcinogenic and non-carcinogenic health effects in the drier seasons than the wet season due to ingestion of nickel, arsenic, cadmium and lead.

Correction to: Exposure to arsenic in utero is associated with various types of DNA damage and micronuclei in newborns: a birth cohort study.

Following publication of the original article [1], the author reported that incorrect version of Tables 1, 3, 5 and 6 were published.

Exposure to arsenic in utero is associated with various types of DNA damage and micronuclei in newborns: a birth cohort study.

BACKGROUND: Growing evidence indicates that in utero arsenic exposures in humans may increase the risk of adverse health effects and development of diseases later in life. This study aimed to evaluate potential health risks of in utero arsenic exposure on genetic damage in newborns in relation to maternal arsenic exposure. METHODS: A total of 205 pregnant women residing in arsenic-contaminated areas in Hanam province, Vietnam, were recruited. Prenatal arsenic exposure was determined by arsenic concentration in mother's toenails and urine during pregnancy and in umbilical cord blood collected at delivery. Genetic damage in newborns was assessed by various biomarkers of early genetic effects including oxidative/nitrative DNA damage (8-hydroxydeoxyguanosine, 8-OHdG, and 8-nitroguanine), DNA strand breaks and micronuclei (MN) in cord blood. RESULTS: Maternal arsenic exposure, measured by arsenic levels in toenails and urine, was significantly increased (p <  0.05) in subjects residing in areas with high levels of arsenic contamination in drinking water. Cord blood arsenic level was significantly increased in accordance with maternal arsenic exposure (p <  0.001). Arsenic exposure in utero is associated with genotoxic effects in newborns indicated as increased levels of 8-OHdG, 8-nitroguanine, DNA strand breaks and MN frequency in cord blood with increasing levels of maternal arsenic exposure. Maternal toenail arsenic level was significantly associated with all biomarkers of early genetic effects, while cord blood arsenic levels associated with DNA strand breaks and MN frequency. CONCLUSIONS: In utero arsenic exposure is associated with various types of genetic damage in newborns potentially contributing to the development of diseases, including cancer, later in life.

Hypomethylation of inflammatory genes (COX2, EGR1, and SOCS3) and increased urinary 8-nitroguanine in arsenic-exposed newborns and children.

Early-life exposure to arsenic increases risk of developing a variety of non-malignant and malignant diseases. Arsenic-induced carcinogenesis may be mediated through epigenetic mechanisms and pathways leading to inflammation. Our previous study reported that prenatal arsenic exposure leads to increased mRNA expression of several genes related to inflammation, including COX2, EGR1, and SOCS3. This study aimed to investigate the effects of arsenic exposure on promoter DNA methylation and mRNA expression of these inflammatory genes (COX2, EGR1, and SOCS3), as well as the generation of 8-nitroguanine, which is a mutagenic DNA lesion involved in inflammation-related carcinogenesis. Prenatally arsenic-exposed newborns had promoter hypomethylation of COX2, EGR1, and SOCS3 in cord blood lymphocytes (p<0.01). A follow-up study in these prenatally arsenic-exposed children showed a significant hypomethylation of these genes in salivary DNA (p<0.01). In vitro experiments confirmed that arsenite treatment at short-term high doses (10-100µM) and long-term low doses (0.5-1µM) in human lymphoblasts (RPMI 1788) caused promoter hypomethylation of these genes, which was in concordance with an increase in their mRNA expression. Additionally, the level of urinary 8-nitroguanine was significantly higher (p<0.01) in exposed newborns and children, by 1.4- and 1.8-fold, respectively. Arsenic accumulation in toenails was negatively correlated with hypomethylation of these genes and positively correlated with levels of 8-nitroguanine. These results indicated that early-life exposure to arsenic causes hypomethylation of COX2, EGR1, and SOCS3, increases mRNA expression of these genes, and increases 8-nitroguanine formation. These effects may be linked to mechanisms of arsenic-induced inflammation and cancer development later in life.

Arsenic projects in SE Asia.

Early life exposure to inorganic arsenic is associated with a wide range of malignant and chronic disease outcomes in humans. Prenatal arsenic exposure may give rise to adverse effects on child health and development as arsenic readily passes through the placenta in human beings. The impact of maternal arsenic exposure on fetal gene expression was conducted in pregnant women living in Southern Thailand. Arsenic exposed newborns had significantly higher levels of arsenic in cord blood, and a set of genes associated with numerous biological pathways, including cell signaling, apoptosis, inflammatory and stress response. A slight increase in promoter methylation of p53 in cord blood lymphocytes which correlated with arsenic accumulation in nails was observed in these exposed newborns. A follow-up study on these exposed children showed a significant increase in oxidative DNA damage, measured as 8-hydroxydeoxyguanosine (8-OHdG) in saliva. In addition, levels of urinary 8-OHdG excretion and salivary hOGG1 expression were significantly decreased in exposed children suggesting a defect in repair of 8-OHdG in arsenic-exposed children. Our study indicates that prenatal arsenic and continued exposure through early childhood can trigger various genetic and epigenetic alterations that may lead to disease development later in life.

Oxidative DNA damage and repair in children exposed to low levels of arsenic in utero and during early childhood: application of salivary and urinary biomarkers.

The present study aimed to assess arsenic exposure and its effect on oxidative DNA damage and repair in young children exposed in utero and continued to live in arsenic-contaminated areas. To address the need for biological specimens that can be acquired with minimal discomfort to children, we used non-invasive urinary and salivary-based assays for assessing arsenic exposure and early biological effects that have potentially serious health implications. Levels of arsenic in nails showed the greatest magnitude of difference between exposed and control groups, followed by arsenic concentrations in saliva and urine. Arsenic levels in saliva showed significant positive correlations with other biomarkers of arsenic exposure, including arsenic accumulation in nails (r=0.56, P<0.001) and arsenic concentration in urine (r=0.50, P<0.05). Exposed children had a significant reduction in arsenic methylation capacity indicated by decreased primary methylation index and secondary methylation index in both urine and saliva samples. Levels of salivary 8-OHdG in exposed children were significantly higher (~4-fold, P<0.01), whereas levels of urinary 8-OHdG excretion and salivary hOGG1 expression were significantly lower in exposed children (~3-fold, P<0.05), suggesting a defect in hOGG1 that resulted in ineffective cleavage of 8-OHdG. Multiple regression analysis results showed that levels of inorganic arsenic (iAs) in saliva and urine had a significant positive association with salivary 8-OHdG and a significant negative association with salivary hOGG1 expression.

Effects of arsenic exposure on DNA methylation in cord blood samples from newborn babies and in a human lymphoblast cell line.

BACKGROUND: Accumulating evidence indicates that in utero exposure to arsenic is associated with congenital defects and long-term disease consequences including cancers. Recent studies suggest that arsenic carcinogenesis results from epigenetic changes, particularly in DNA methylation. This study aimed to investigate DNA methylation changes as a result of arsenic exposure in utero and in vitro. METHODS: For the exposure in utero study, a total of seventy-one newborns (fifty-five arsenic-exposed and sixteen unexposed newborns) were recruited. Arsenic concentrations in the drinking water were measured, and exposure in newborns was assessed by measurement of arsenic concentrations in cord blood, nails and hair by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). In the in vitro study, human lymphoblasts were treated with arsenite at 0-100 µM for two, four and eight hours (short-term) and at 0, 0.5 and 1.0 µM for eight-weeks period (long-term). DNA methylation was analyzed in cord blood lymphocytes and lymphoblasts treated with arsenite in vitro. Global DNA methylation was determined as LINE-1 methylation using combined bisulfite restriction analysis (COBRA) and total 5-methyldeoxycytidine (5MedC) content which was determined by HPLC-MS/MS. Methylation of p53 was determined at the promoter region using methylation-specific restriction endonuclease digestion with MspI and HpaII. RESULTS: Results showed that arsenic-exposed newborns had significantly higher levels of arsenic in cord blood, fingernails, toenails and hair than those of the unexposed subjects and a slight increase in promoter methylation of p53 in cord blood lymphocytes which significantly correlated with arsenic accumulation in nails (p < 0.05) was observed, while LINE-1 methylation was unchanged. Short-term in vitro arsenite treatment in lymphoblastoid cells clearly demonstrated a significant global hypomethylation, determined as reduction in LINE-1 methylation and total 5-MedC content, and p53 hypermethylation (p < 0.05). However, a slight LINE-1 hypomethylation and transient p53 promoter hypermethylation were observed following long-term in vitro treatment. CONCLUSIONS: This study provides an important finding that in utero arsenic exposure affects DNA methylation, particularly at the p53 promoter region, which may be linked to the mechanism of arsenic carcinogenesis and the observed increased incidence of cancer later in life.