Transgenerational effects of endocrine disruptors: epigenetics and physiology

Summary

Principal Investigator: Rebecca A Simmons
Abstract: DESCRIPTION (provided by applicant): There is growing evidence that in utero and early developmental exposures to environmental chemicals may play a role in the development of obesity and related metabolic diseases later in life. Endocrine disrupting compounds are exogenous substances that mimic endogenous hormones in the endocrine pathway. Bisphenol-A (BPA) is a chemical plasticizer and xenoestrogen used in the production of polycarbonate plastics and epoxy resins. Human exposure to BPA is ubiquitous at low levels and occurs primarily through the diet. Studies in our laboratory and other investigators have shown that exposure of rodents to BPA during pregnancy results in increased adiposity and impaired glucose tolerance in adulthood. An important mechanism for in utero and early developmental effects of BPA is thought to be altered epigenetic regulation of gene expression. In support of this hypothesis is our preliminary data in mouse that BPA exposure during pregnancy results in loss of imprinting at two genes critical for development and obesity, Igf2 and Snrpn, in the embryo and placenta. These findings lead us to hypothesize that BPA exposure during development alters the epigenetic profile in key cells including the germline, resulting in altered gene expression, an abnormal phenotype, and transgenerational transmission of the phenotype. Other than the placenta, we cannot obtain target tissues such as islets, liver, or fat from humans during development. Thus an animal model can provide insight into mechanisms that can be later explored in the human. We propose the following specific aims: Specific Aim 1 will assess the epigenome of F1 offspring exposed to BPA in utero as well as the F2-F3 generations. In addition to testing the expression and DNA methylation of imprinted genes, we will assay genome-wide DNA methylation changes and key histone modifications in F1-F3 offspring. The F1-F3 generations will also be metabolically phenotyped and germline of F2 and F3 epigenetically assayed. Specific Aim 2 will ascertain whether BPA exposure of males during puberty and early adulthood alters the germline and leads to transgenerational transmission of an altered epigenotype and abnormal phenotype. In Specific Aim 3 we will determine whether low dose BPA exposure in combination with DEHP, and vinclozolin alters the epigenome in the germline and leads to transgenerational transmission of an abnormal phenotype. Through the comprehensive analyses in the in vivo model, the results of the proposed project will build a solid standard for extrapolation of effects and mode of action to other classes of endocrine disrupting chemicals that are present in food and are identified as potential inducers of obesity and related metabolic diseases later in life. The proof of the principle of prenatal programming by environmental contaminants may change our awareness of critical assessment of the risk of such compounds.
Funding Period: -----------------201 - ----------------2018
more information: NIH RePORT

Detail Information

Research Grants30

  1. UC Berkeley/Stanford Children's Enviromental Health Center
    Gary M Shaw; Fiscal Year: 2013
    ..7) To support the data management and QA/QC operations of CHAPS-SJV. 8) To support and implement the data sharing plan. 9) To support the annual CEHC meetings and the travel of CHAPS-SJV investigators to these meetings. ..
  2. Lifecourse Exposures &Diet: Epigenetics, Maturation &Metabolic Syndrome
    KAREN EILEEN PETERSON; Fiscal Year: 2013
    ..Career development and training activities will draw upon extensive institutional resources and will be fully integrated with the Center's Research Projects and Cores. ..
  3. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  4. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  5. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  6. Southern California Children's Enviromental Health Center (SC-CEHC)
    Rob S McConnell; Fiscal Year: 2013
    ....
  7. In Utero Exposure to Bisphenol A: Effects on the Fetal Epigenome
    DANA DOLINOY; Fiscal Year: 2013
    ....
  8. CENTER FOR CHILD ENVIRONMENTAL HEALTH RISKS RESEARCH
    Elaine M Faustman; Fiscal Year: 2013
    ..The Center also includes junior investigators, new scientists since the 2003 Center renewal, and a Faculty Development Investigator. The Internal Steering Committee in comprised of a number of Center investigators and directors. ..
  9. Prepubertal Stress, Windows of Risk &Sex Bias for Affective Disturbance
    C NEILL NEILL EPPERSON; Fiscal Year: 2013
    ..The Center would provide an intellectual platform with important resources to encourage established investigators, and their mentees, to consider sex and gender as crucial factors in their research. ..
  10. Prenatal Events-Postnatal Consequences
    James C Rose; Fiscal Year: 2013
    ..Therefore our work may promote the identification of new, early intervention strategies to reduce the risk of hypertension as well as renal and metabolic abnormalities in antenatal steroid exposed individuals. ..
  11. Epigenomics of Bisphenol A Exposure and Disease Risk
    Tim H M Huang; Fiscal Year: 2013
    ..Epigenomic mapping of these CpG islands may identify potential biomarkers that are used as environmental sensors for monitoring human exposures to environmental estrogens. ..
  12. Structural Cell Biology of DNA Repair Machines
    John A Tainer; Fiscal Year: 2013
    ..abstract_text> ..
  13. Birth, Muscle Injury and Pelvic Floor Dysfunction
    John O L Delancey; Fiscal Year: 2013
    ..It will establish the scientific basis for new strategies to improve treatment, identify important prevention opportunities, and train a new generation of researchers. ..
  14. Effects of fetal bisphenol A exposure on mouse epigenome
    Martha Susiarjo; Fiscal Year: 2013
    ..The mouse will be used as a model system in the proposed studies to determine the potential etiology of human diseases with underlying environmental causes. ..
  15. The UCSF Pregnancy Exposures to Environmental Chemicals (PEEC) Children's Center
    Tracey J Woodruff; Fiscal Year: 2013
    ..Finally, the Administrative Core will work closely with a program evaluator, to monitor the progress of the PEEC Children's Center and ensure the achievement of its goals. ..
  16. Functional Analysis of the Embryonic Epigenome in a Non-rodent Model
    Mark E Westhusin; Fiscal Year: 2013
    ....
  17. Prenatal stress: the epigenetic basis of maternal and perinatal effects
    Benjamin Tycko; Fiscal Year: 2013
    ....
  18. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  19. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  20. Human Exposure to Bisphenol A, Phthalates and Fertility, Pregnancy Outcomes
    Russ B Hauser; Fiscal Year: 2013
    ..abstract_text> ..
  21. Beryllium: Exposure Immune and Genetic Mechanisms
    Lee S Newman; Fiscal Year: 2013
    ..The productivity and continuance demonstrate quality, commitment and ability to work together. PROGRAM AS INTERGRATED EFFORT ..
  22. DETECTION AND MODELS OF TOXICANT EXPOSURE
    Robert H Tukey; Fiscal Year: 2013
    ..Our combined efforts are anticipated to provide new insights into the molecular mechanisms that lead to environmental illness, and improve our understanding of the consequences of exposure to Superfund site contaminants. ..
  23. Center for Nanobiology and Predictive Toxicology
    ANDRE ELIAS NEL; Fiscal Year: 2013
    ....
  24. Molecular and Clinical Pharmacology of Retinopathy of Prematurity
    Jacob V Aranda; Fiscal Year: 2013
    ..The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness. ..