Is it possible that fetal exposure to chemicals contained in everyday household objects such as carpets, paints, or cookware could be responsible for causing obesity in children and adults? It’s a question that scientists have been asking for a number of years, and mounting evidence in animal models—as well as a few epidemiological studies—suggests that some types of environmental chemicals, known as endocrine disrupting chemicals (EDCs), can affect the body’s hormonal control of hunger and satiety, interfere with normal homeostatic control mechanisms, and possibly cause obesity.
Researchers at the Cedars-Sinai Board of Governors Regenerative Medicine have now developed a human induced pluripotent stem cell (iPSC)-derived cell platform as a model to show that a number of these EDCs do disrupt normal signaling between the developing digestive system and brain to trigger how we feel “full” after eating. The studies, led by Dhruv Sareen, Ph.D., assistant professor of biomedical sciences and director of the Induced Pluripotent Stem Cell Core Facility, found that EDCs impact biochemical pathways and mitochondrial function, which combine to disrupt metabolic function in endocrine cells. They report their findings in Nature Communications, in a paper entitled “Endocrine Disruptors Induce Perturbations in Endoplasmic Reticulum and Mitochondria of Human Pluripotent Stem Cell Derivatives.”
Normal endocrine-mediated control of feeding behavior involves communication between hormone-secreting cells in the gastrointestinal tract, and neuroendocrine cells in the hypothalamus, which regulates metabolism and appetite, Dr. Sareen and colleagues explain. Hypothalamic neuropeptidergic neurons receive endocrine signals from different parts of gut, including gastrin and ghrelin from the stomach and peptide YY from the midgut and intestine, and this communication mediates orexigenic (appetite increasing) or anorexigenic (appetite reducing) responses.
Prior research has suggested that persistent fetal exposure to “obesogenic” EDCs during critical stages of stem cell development can alter normal metabolic control in genetically predisposed individuals, and this will effectively “set them up for long-term obesity,” the Cedars-Sinai team writes. “Hence, perturbations during development due to environmental factors such as EDCs may have a role in dysfunction of the gut–brain interactions thereby bringing about feeding disorders and obesity.”
However, testing whether obesogenic EDCs can alter signaling between gut and hypothalamus to cause obesity in humans has been problematic because scientists haven’t had a suitable experimental human fetal cell or tissue model. The Cedars-Sinai Institute team has now overcome that hurdle, and developed a human hormone-producing cell model from iPSCs as a human test system for EDCs. They used the system to investigate how EDCs impact on hormonal signaling between developing endocrine-active human gut epithelium and neuroendocrine cells in the brain’s hypothalamus.
The team found that each of three environmental EDCs, butylhydroxytoluene (BHT), perfluorooctanoic acid (PFOA), and tributyltin (TBT) disrupted normal production and secretion of appetite-control hormones. BHT was the worst-offending. The chemical is an antioxidant that is added to breakfast cereals and other foods to prevent them from becoming rancid and is also added to a range of personal care products. The use of BHT is restricted in the EU.
PFOA is a polymer used to manufacture nonstick cookware, stain-resistant carpets, and waterproof clothing. Figures cited by the authors suggest that about 98% of the U.S population will have detectable levels of PFOA in their blood, and epidemiological evidence indicates that exposure is associated with disorders ranging from high cholesterol levels, to thyroid diseases, ulcerative colitis, and reproductive problems. Late last year, the U.S. Environmental Protection Agency issued new drinking health advisories for PFOA.
TBT is an antifouling agent that was commonly used in paint on ships, is also present in house dust, and accumulates in seafood, the Cedars-Sinai researchers note. The chemical has now been banned by the International Maritime Organization.
Exposing the gut and brain cells to each of these three EDCs induced endoplasmic reticulum (ER) stress, disturbed NF-κB and p53 signaling, and also damaged mitochondrial function by reducing mitochondrial respiratory gene expression, spare respiratory capacity, and adenosine triphosphate (ATP) levels. Impaired mitochondrial function is linked with long-term metabolic dysfunction in obesity and type 2 diabetes, the authors state.
When the cells were exposed to physiologically relevant levels of all three chemicals together, the detrimental effects were amplified. When each chemical was tested on its own, BHT was the worst-offending of the three. And because harmful effects of the three chemicals occurred in young cells, the findings indicate that altered hormonal effects could be set in motion in the fetus, from a very early stage of development.
The new iPSC-derived cell system will allow scientists to study the effects of new and existing environmental chemicals, the Cedars-Sinai team suggests. They point out that of the thousands of chemicals that U.S. citizens are exposed, only about 2% have undergone a safety review by government scientists.
“This is a landmark study that substantially improves our understanding of how endocrine disruptors may damage human hormonal systems and contribute to the obesity epidemic in the U.S.,” stated Clive Svendsen, Ph.D., director of the institute and the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine.
“Although it remains to be demonstrated how long-term ER stress, perturbation of NF-κB p65 and p53 signaling, and mitochondrial dysfunction in developing endocrine cells may contribute to metabolic diseases like obesity and type 2 diabetes, the platform described here has enormous potential for screening the developmental impact of human exposure to harmful endocrine disrupting chemicals in the environment,” the authors conclude.