Endocrine disruption by organotins in obesity and diabetes

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DESCRIPTION (provided by applicant): This is a competitive supplemental application to parent grant ES-015849 in response to Notice Number (NOTOD-09-058) entitled: "NIH Announces the Availability of Recovery Act Funds for Competitive Revision". Prenatal and early postnatal events such as maternal nutrition, drug, and chemical exposure are received, remembered, and then manifested in health consequences later in life. The obesity epidemic costs more than $75 billion annually in the US, primarily by increasing health care costs. Emerging evidence supports an important role for environmental factors in obesity. Among these is exposure to endocrine disrupting chemicals. Our published work identified tributyltin (TBT) as an environmental "obesogen" that predisposes exposed individuals to weight gain. In utero TBT exposure leads to long-term metabolic dysfunctions, enhanced fat accumulation, and increased risk of obesity. These data support the model that TBT acts via inappropriate modulation of the "master regulator" of mammalian adipocyte differentiation - the peroxisome proliferator activated receptor gamma (PPAR?) signaling pathway. Preliminary results reveal that prenatal TBT exposure alters the fate of multipotent mesenchymal stem cells (MSCs) by diverting them to an adipocyte lineage and that epigenetic modification of its promoter leads to up-regulation of a key PPAR? target gene. We hypothesize that prenatal activation of PPAR? by TBT is epigenetically imprinted in the stem cell compartment memory triggering the migration and differentiation of MSCs to fat depots during development. Two specific aims are proposed to test this hypothesis: 1) Does prenatal TBT exposure affect multipotent stromal cell fate in vivo? 2) How is prenatal TBT exposure imprinted in the multipotent stromal cell compartment? The proposed work will facilitate rapid progress in understanding the modulation of developmental pathways controlling the prenatal programming of MSC fate by and how exposure to environmental obesogens alters this fate. PUBLIC HEALTH RELEVANCE: Obesity is a major public health problem. We propose to elucidate how maternal programming of adipose tissue development is influenced by endocrine disrupting chemicals that activate PPAR? and whether circulating MSCs contribute to adipose development. The successful completion of this research will make important contributions to understanding the maternal programming of obesity, how obesogens affect this process, and what is the contribution of altered stem cell programming.