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Nat Commun. 2017 Aug 9;8(1):219. doi: 10.1038/s41467-017-00254-8.

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

Author information

1
Board of Governors-Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
2
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
3
Department of Medicine, University of California, Los Angeles, CA, 90048, USA.
4
Metabolism and Mitochondrial Research Core, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
5
Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
6
Board of Governors-Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. dhruv.sareen@cshs.org.
7
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. dhruv.sareen@cshs.org.
8
Department of Medicine, University of California, Los Angeles, CA, 90048, USA. dhruv.sareen@cshs.org.
9
iPSC Core, The David Janet Polak Foundation Stem Cell Core Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. dhruv.sareen@cshs.org.

Abstract

Persistent exposure to man-made endocrine disrupting chemicals during fetal endocrine development may lead to disruption of metabolic homeostasis contributing to childhood obesity. Limited cellular platforms exist to test endocrine disrupting chemical-induced developmental abnormalities in human endocrine tissues. Here we use an human-induced pluripotent stem cell-based platform to demonstrate adverse impacts of obesogenic endocrine disrupting chemicals in the developing endocrine system. We delineate the effects upon physiological low-dose exposure to ubiquitous endocrine disrupting chemicals including, perfluoro-octanoic acid, tributyltin, and butylhydroxytoluene, in endocrine-active human-induced pluripotent stem cell-derived foregut epithelial cells and hypothalamic neurons. Endocrine disrupting chemicals induce endoplasmic reticulum stress, perturb NF-κB, and p53 signaling, and diminish mitochondrial respiratory gene expression, spare respiratory capacity, and ATP levels. As a result, normal production and secretion of appetite control hormones, PYY, α-MSH, and CART, are hampered. Blocking NF-κB rescues endocrine disrupting chemical-induced aberrant mitochondrial phenotypes and endocrine dysregulation, but not ER-stress and p53-phosphorylation changes.Harmful chemicals that disrupt the endocrine system and hormone regulation have been associated with obesity. Here the authors apply a human pluripotent stem cell-based platform to study the effects of such compounds on developing gut endocrine and neuroendocrine systems.

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