Altered Igf2 imprint leads to accelerated adipogenesis and early onset of metabolic syndrome in male mice following gestational arsenic exposure.
Chemosphere
; 352: 141493, 2024 Mar.
Article
en En
| MEDLINE
| ID: mdl-38368966
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 Metabolic Syndrome (MetS). In this work, we have assessed the effects of preconceptional plus gestational arsenic exposure on the developmental programming of MetS in offspring. In our study, only gestational arsenic exposure led to reduced birth weight, followed by catch-up growth, adiposity, elevated serum triglycerides levels, and hyperglycemia in male offspring. Significant adipocyte 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 individuals 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 cells (AdSCs) from exposed progeny had increased proliferation and adipogenic potential with excess 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 (p-IGF1R) and its upstream activator Insulin-like growth factor-2 (IGF2). Overexpression of Igf2 was found to be due to arsenic-mediated DNA hypermethylation at the imprinting control region (ICR) located -2kb to -4.4 kb upstream of the H19 gene which caused a reduction in the conserved zinc finger protein (CTCF) occupancy. This further led to persistent activation of the MAPK signaling cascade and enhanced adipogenesis leading to the early onset of MetS in the offspring.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Arsénico
/
Síndrome Metabólico
Límite:
Animals
Idioma:
En
Revista:
Chemosphere
Año:
2024
Tipo del documento:
Article
País de afiliación:
India
Pais de publicación:
Reino Unido