Developmental origin of health and disease postulates that the footprints of early life exposure are followed as an endowment of risk for adult diseases. Epidemiological and experimental evidence suggest that an adverse fetal environment can affect the health of offspring throughout their lifetime. Exposure to endocrine disrupting chemicals (EDCs) during fetal development can affect the hormone system homeostasis, resulting in a broad spectrum of adverse health outcomes. In the present review, we have described the effect of prenatal EDCs exposure on cardio-metabolic-renal health, using the available epidemiological and experimental evidence. We also discuss the potential mechanisms of their action, which include epigenetic changes, hormonal imprinting, loss of energy homeostasis, and metabolic perturbations. The effect of prenatal EDCs exposure on cardio-metabolic-renal health, which is a complex condition of an altered biological landscape, can be further examined in the case of other environmental stressors with a similar mode of action.
Developmental exposure to environmental pollutants has been shown to promote adverse health outcomes in offspring. Exposure to heavy metals such as arsenic which also has endocrine disrupting activity is being increasingly linked with cancers, diabetes and lately with the metabolic syndrome (MetS). In this work we have assessed the effects of only prenatal arsenic exposure on developmental programming of MetS in offspring. In our study, only prenatal arsenic exposure led to reduced birth weight which was followed by catch-up growth, adiposity, elevated serum triglycerides levels and hyperglycemia in male offspring. Significant adipocytes dysfunction was observed in offspring with increased hypertrophy, insulin resistance, and chronic inflammation in epididymal white adipose tissue. Adipose tissue regulates the metabolic health of individual and its dysfunction resulted in elevated serum levels of metabolism regulating adipokines (Leptin, Resistin) and pro-inflammatory cytokines (PAI-1, TNFα). The progenitor adipose derived stem/stromal cells (AdSCs) from exposed progeny had increased proliferation and adipogenic potential with increased lipid accumulation. We also found increased activation of Akt, ERK1/2 & p38 MAPK molecules in arsenic exposed AdSCs along with increased levels of phospho-Insulin-like growth factor-1 receptor and its upstream activator Insulin-like growth factor-2 (IGF2). Overexpression of IGF2 was found to be due to arsenic mediated DNA hypermethylation at ICR region located − 2kb to -4.4kb upstream of H19 Transcription start site (TSS) which caused reduction in the conserved zinc finger protein (CTCF) occupancy. This further led to persistent activation of AKT & MAPK signaling cascade and enhanced adipogenesis leading to early onset of metabolic syndrome in the offspring.
Arsenic (As) exposure is progressively associated with chronic kidney disease (CKD), a leading public health concern present worldwide. The adverse effect of As exposure on the kidneys of people living in As endemic areas have not been extensively studied. Furthermore, the impact of only prenatal exposure to As on the progression of CKD also has not been fully characterized. In the present study, we examined the effect of prenatal exposure to low doses of As 0.04 and 0.4 mg/kg body weight (0.04 and 0.4 ppm, respectively) on the progression of CKD in male offspring using a Wistar rat model. Interestingly, only prenatal As exposure was sufficient to elevate the expression of profibrotic (TGF-β1) and proinflammatory (IL-1α, MIP-2α, RANTES, and TNF-α) cytokines at 2-day, 12- and 38-week time points in the exposed progeny. Further, alteration in adipogenic factors (ghrelin, leptin, and glucagon) was also observed in 12- and 38-week old male offspring prenatally exposed to As. An altered level of these factors coincides with impaired glucose metabolism and homeostasis accompanied by progressive kidney damage. We observed a significant increase in the deposition of extracellular matrix components and glomerular and tubular damage in the kidneys of 38-week-old male offspring prenatally exposed to As. Furthermore, the overexpression of TGF-β1 in kidneys corresponds with hypermethylation of the TGF-β1 gene-body, indicating a possible involvement of prenatal As exposure-driven epigenetic modulations of TGF-β1 expression. Our study provides evidence that prenatal As exposure to males can adversely affect the immunometabolism of offspring which can promote kidney damage later in life.
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