Prenatal and early childhood exposure to arsenic has been associated with a wide range of chronic diseases, including cancer and metabolic diseases, later in adult life (Tokar et al., 2011; Hawkesworth et al., 2013). Large population-based prospective studies of children in rural Bangladesh (Hawkesworth et al., 2013) and young adults in Chile (Yuan et al., 2007) showed that in utero and early-life exposure to arsenic via contaminated water was associated with increased risk of cardiovascular diseases. In addition, studies from Taiwan, Bangladesh, Mexico, and the United States demonstrated that chronic exposure to arsenic altered several cardiometabolic parameters resulting in increased risk of developing metabolic diseases during adulthood (Maull et al., 2012; Grau-Perez et al., 2017). At present, the mechanisms underlying the pathogenesis of metabolic diseases in relation to prenatal exposure to arsenic exposure have not been characterized and are poorly understood.

Prenatal exposure to toxicants, especially arsenic, could also be a factor contributing to the early-life origin of metabolic diseases possibly by altering fetal developmental processes that regulate the homeostasis of adipose tissue (Wang et al., 2014). During fetal development, mature adipocytes are differentiated from mesenchymal stem cells (MSCs) (Shao et al., 2017). Accumulated data demonstrated that arsenic exposure suppressed adipogenesis of both human bone marrow MSCs (Yadav et al., 2013) and mouse adipose tissue MSCs (Shearer et al., 2017). This evidence suggests that MSCs could be another target of arsenic toxicity. The process of adipogenesis involves sequential changes in the expression of specific genes that determine the adipocyte-specific phenotype. Several transcription factors that regulate adipocyte differentiation have been identified. Peroxisome proliferator-activated receptor γ (PPARγ), a master regulator, is necessary to induce adipogenic differentiation by inducing the expression of adipocyte-specific genes including, but not limited to, fatty acid-binding protein (aP2) and glucose transporter-4 (GLUT4).

Accumulated evidence from both preclinical and clinical studies indicated that adipose tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines. Thus, an imbalance in the adipokine profile mediated by dysfunctional adipocytes that leads to chronic inflammation is the major etiologic component of the pathogenesis of metabolic diseases. Among different adipokines, the levels of Leptin (a pro-inflammatory adipokine) and Adiponectin (an anti-inflammatory adipokine) are widely used for predicting the incidence and severity of metabolic diseases (Falahi et al., 2015; Liu et al., 2020). In addition, hypersecretion of inflammatory cytokines by dysfunctional adipocytes, such as the interleukin (IL): IL-6, -8, and -1β, leads to insulin resistance, which could facilitate both the onset and progression of metabolic and vascular diseases (Veljić et al., 2018). When compared to non-obese subjects, a significant decrease in the expression of genes encoding Adiponectin (ADIPOQ), along with the increased expression of genes encoding Leptin (LEP) and inflammatory genes such as IL-6 (CXCL6) and IL-1β (IL1β), was observed in visceral adipose tissue from obese subjects (Coín-Aragüez et al., 2018). Analysis of the production and release of IL-8 from human adipose tissue suggests that the increased expression of the gene encoding IL-8 (CXCL8) may account for the observed increased plasma IL-8 levels in obese subjects (Bruun et al., 2004). Furthermore, increased levels of plasma IL-6 and IL-8 may contribute to the activation of monocytes, another key effector cell which initiates the formation of atherosclerotic plaques leading to the development of atherosclerosis (Reddy et al., 2019).

Arsenic toxicity is very complex and affects multiple organs throughout the body. One possible mechanism of arsenic toxicity involves alterations in DNA methylation profiles leading to aberrant gene expression (Bailey et al., 2016). Our previous study showed that both newborns and young children who were continuously exposed to arsenic starting in utero showed increased expression of several inflammatory genes (COX2, EGR1, and SOCS3) resulting from significant hypomethylation in their promoter regions (Phookphan et al., 2017). These effects may be linked to the mechanisms of arsenic-induced chronic inflammation later in life. Chronic inflammation is recognized as another important mechanism involved in pathogenesis of several chronic diseases. Thus, increased expression of genes related to inflammation mediated by arsenic exposure could contribute to the development of metabolic diseases. In addition, alterations in the expression levels of genes encoding PPARγ (PPARG), aP2 (FABP4), GLUT4 (SLC2A4), Leptin (LEP), Adiponectin (ADIPOQ), IL-6 (CXCL6), IL-8 (CXCL8), and IL-1β (IL1β) are known to play a crucial role in the pathogenesis of metabolic diseases (Veljić et al., 2018; Trojnar et al., 2019; Al-Hamodi et al., 2014). It is, however, unclear whether arsenic exposure, starting in utero and continuing throughout childhood, can alter the expression of these genes.

This study aims to examine the effect of arsenic exposure in utero on the expression of genes associated with the pathogenesis of metabolic diseases (PPARG, FABP4, SLC2A4, LEP, and ADIPOQ) in the newborns and children from our birth cohort. These results were then confirmed by in vitro studies using an umbilical cord derived MSC cells (UC-MSCs) as a surrogate for fetal stem cells. The direct effect of arsenite treatment on adipogenic differentiation of fetal MSCs was assessed. Further, the expression pattern of the aforementioned genes that are known to be associated with metabolic diseases was determined in differentiated adipocytes along with the expression levels of inflammatory related genes (CXCL6, CXCL8, and IL1β).