Endocrine disruptors induce perturbations in endoplasmic reticulum and mitochondria of human pluripotent stem cell...

Area of Science:

• Developmental biology
• Endocrinology
• Toxicology

Background:

• Man-made endocrine disrupting chemicals (EDCs) are linked to metabolic homeostasis disruption and childhood obesity.
• Existing cellular models are insufficient for studying EDC impacts on human endocrine development.

Purpose of the Study:

• To utilize a human induced pluripotent stem cell (hiPSC)-based platform to investigate the adverse effects of obesogenic EDCs on the developing human endocrine system.
• To delineate the molecular and cellular mechanisms by which EDCs disrupt endocrine function and contribute to metabolic abnormalities.

Main Methods:

• Development of an hiPSC-based cellular platform using foregut epithelial cells and hypothalamic neurons.
• Exposure of the hiPSC model to low doses of common EDCs (perfluoro-octanoic acid, tributyltin, butylhydroxytoluene).
• Analysis of cellular responses including endoplasmic reticulum (ER) stress, NF-κB and p53 signaling, mitochondrial function, and hormone secretion.

Main Results:

• EDCs induced ER stress, perturbed NF-κB and p53 signaling pathways, and diminished mitochondrial gene expression while sparing respiratory capacity and ATP levels.
• Normal production and secretion of appetite-regulating hormones (PYY, α-MSH, CART) were significantly hampered.
• Blocking NF-κB signaling partially rescued mitochondrial dysfunction and endocrine dysregulation but did not affect ER stress or p53 phosphorylation.

Conclusions:

• The hiPSC-based platform effectively models EDC-induced developmental abnormalities in human endocrine tissues.
• Obesogenic EDCs disrupt critical cellular pathways (ER stress, mitochondrial function, signaling pathways) essential for normal endocrine development and metabolic homeostasis.
• Targeting NF-κB signaling may offer a therapeutic avenue for mitigating some EDC-induced endocrine disruptions, though further research is needed to address ER stress and p53-related effects.