Altered IGF2 imprint leads to accelerated adipogenesis and early onset of metabolic syndrome in mice following prenatal arsenic exposure

Abstract

Abstract 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.