Studies in animal models have linked direct exposures to endocrine disrupting chemicals (EDCs) with the onset of disease in descendants of the exposed individuals. Many groups have demonstrated such transgenerational effects of chemical exposures, which are proposed to be examples of epigenetic inheritance. Although transgenerational effects have substantial support in the literature, the concept of inheritance in the absence of DNA sequence changes is controversial because the underlying mechanisms have not been satisfactorily explained. If we do not know how transgenerational inheritance of environmental exposures is transmitted, how can we incorporate the effects of these chemicals on disease burden into risk assessment paradigms that adequately protect public health? How can we determine which chemicals may have transgenerational effects? We have developed a transgenerational model for obesity. When pregnant F0 female mice are treated with environmentally-relevant (nM) doses of TBT via their drinking water, increased fat accumulation can be detected in at least the next four generations of descendents (the F1-F4 generations), even on a low-fat diet. Male F4 descendents of pregnant F0 dams treated with TBT throughout gestation developed a transgenerational ?thrifty phenotype?: they were resistant to fat loss during fasting, rapidly gained weight when dietary fat was increased modestly and retained this fat despite being returned to a normal, low- fat diet. Our published and preliminary results led us to propose a new model for transgenerational inheritance - that prenatal TBT exposure altered chromatin structure and accessibility, leading to regional changes in blocks of methylated DNA and differential expression of important metabolic genes, including the satiety hormone, leptin. We propose a comprehensive series of experiments designed to test the hypothesis that TBT induces transgenerational obesity by changing chromatin structure which is transmitted via the germ cells to subsequent generations. We propose the following Specific Aims to test this novel hypothesis:
Aim 1 : Identify what changes in genomic structure are elicited by TBT exposure in germ cells and how these are transmitted down the generations.
Aim 2 : What is the role of gonadal somatic cells in the transgenerational phenotype.
Aim 3 : What changes does ancestral TBT exposure elicit in the metabolome and can these be used to determine why the transgenerational obesity phenotype appears to be male-specific? Delineating these molecular mechanisms will greatly our knowledge of gene-environment interactions, should lay the groundwork for risk assessment that includes the contributions of transgenerational effects and will provide insights into how obesity can be prevented and the obesity epidemic curtailed - an important and timely public health issue.

Public Health Relevance

Obesity is a major public health problem. We propose to elucidate how the effects of prenatal obesogen exposure are transmitted, leading to a transgenerational thrifty phenotype. The successful completion of this research will make important contributions to understanding epigenetic transgenerational inheritance, how obesity is transmitted down the generations and will provide insights into how obesity can be prevented and the obesity epidemic curtailed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES023316-06
Application #
9597165
Study Section
Systemic Injury by Environmental Exposure (SIEE)
Program Officer
Schug, Thaddeus
Project Start
2013-09-01
Project End
2023-04-30
Budget Start
2018-08-01
Budget End
2019-04-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
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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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