This is an R01 application submitted in response to RFA-ES-12-006, Transgenerational Inheritance in Mammals after Environmental Exposure. 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 $208 billion annually in the US in additional health care costs associated with obesity-related diseases. Emerging evidence supports an important role for environmental factors in obesity. Among these is exposure to endocrine disrupting chemicals (EDCs). 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. Our published and preliminary results reveal that prenatal TBT exposure alters the fate of multipotent mesenchymal stem cells (MSCs) by diverting them to an adipocyte lineage at the expense of bone and that this reprogramming is transgenerational, persisting through at least the F3 generation after F0 exposure. The transgenerational inheritance of the effects of TBT exposure suggests that these effects are epigenetic and permanent and that epigenetic modification of the promoter leads to up-regulation of a key PPAR? target gene. We hypothesize that prenatal exposure to TBT is epigenetically engraved in the memory of the MSC compartment, reprogramming MSCs toward the adipogenic and away from the osteogenic lineage.
Three specific aims are proposed to test this hypothesis: 1) which genes are epigenetically modified by prenatal TBT exposure to elicit altered expression in MSCs that promotes the adipocyte lineage at the expense of the osteogenic lineage? 2) How does TBT exert transgenerational effects on lineage allocation in MSCs?, 3) Are postnatal effects of TBT exposure mediated by epigenetic alterations? We will use state-of-the-art genomic, epigenomic and transcriptomic analyses to address these questions. The proposed work will provide a deep understanding of how TBT (and likely other obesogens) act transgenerationally to reprogram MSC fate and will identify critical developmental windows for TBT exposure.

Public Health Relevance

Obesity is a major public health problem. We propose to elucidate how maternal and early life exposure to obesogens epigenetically reprograms the multipotent mesenchymal stem cell compartment to favor the adipogenic at the expense of the osteogenic pathways. The successful completion of this research will make important contributions to understanding the developmental programming of obesity, how obesogens affect this process, and what is the contribution of altered stem cell programming.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZES1)
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Schug, Thaddeus
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University of California Irvine
Anatomy/Cell Biology
Schools of Arts and Sciences
United States
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Chamorro-GarcĂ­a, Raquel; Shoucri, Bassem M; Willner, Sigal et al. (2018) Effects of Perinatal Exposure to Dibutyltin Chloride on Fat and Glucose Metabolism in Mice, and Molecular Mechanisms, in Vitro. Environ Health Perspect 126:057006
Taylor, Julia A; Shioda, Keiko; Mitsunaga, Shino et al. (2018) Prenatal Exposure to Bisphenol A Disrupts Naturally Occurring Bimodal DNA Methylation at Proximal Promoter of fggy, an Obesity-Relevant Gene Encoding a Carbohydrate Kinase, in Gonadal White Adipose Tissues of CD-1 Mice. Endocrinology 159:779-794
Chamorro-Garcia, Raquel; Diaz-Castillo, Carlos; Shoucri, Bassem M et al. (2017) Ancestral perinatal obesogen exposure results in a transgenerational thrifty phenotype in mice. Nat Commun 8:2012
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Bornman, Maria S; Aneck-Hahn, Natalie H; de Jager, Christiaan et al. (2017) Endocrine Disruptors and Health Effects in Africa: A Call for Action. Environ Health Perspect 125:085005
Janesick, Amanda S; Dimastrogiovanni, Giorgio; Chamorro-Garcia, Raquel et al. (2017) Reply to ""Comment on 'On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens'"". Environ Health Perspect 125:A12-A14
Shoucri, Bassem M; Martinez, Eric S; Abreo, Timothy J et al. (2017) Retinoid X Receptor Activation Alters the Chromatin Landscape To Commit Mesenchymal Stem Cells to the Adipose Lineage. Endocrinology 158:3109-3125

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