THE EFFECT OF DIOXINS ON GLUCOSE HOMEOSTASIS IN MURINE TESTES

Summary

Principal Investigator: KENAN RIFAT OMURTAG
Abstract: DESCRIPTION (provided by applicant): Dioxins represent a class of highly toxic and widely dispersed environmental hazards that have been implicated in aberrations in male reproductive cell function and even adverse pregnancy outcomes associated with paternal exposure. Many of these effects take several years to manifest. Investigators have attempted to characterize the toxicity of dioxin binding at a cellular and molecular level, but to date the mechanism remains incompletely understood. The objective of this study is to determine whether the mechanism of action of dioxin exposure on male gametes involves communication between the aryl hydrocarbon receptor (AhR) and glucose transport. In addition we seek to determine if dioxin exposure affects gene expression in the germ cells and perhaps stem cells at different stages of spermatogenesis. These changes may not manifest until much later relative to exposure and thus may explain the paternal effects on offspring and pregnancy outcome. Previous studies suggest that the AhR receptor, also known as the "dioxin receptor," may play a role in decreased glucose utilization in epithelial cells in various other tissues of the body. Our preliminary data show that glucose transporters play a significant role in the testes and on spermatogenesis and that certain cell signaling proteins/receptors play a role in modulating glucose homeostasis in these germ cells at the various stages of spermatogenesis. Previous study in our lab has shown several functional detriments to spermatogenesis, sperm motility, and fertilization capability in mice affected with disruptions in glucose homeostasis. Moreover we have established a Laser Microdissection protocol for testis sections and have successful validate our techniques. We hypothesize that dioxin exposure disrupts spermatogenesis through activation of the AhR receptor and subsequent disruption of glucose transporter (GLUT) isoforms adversely affects essential cellular function and development. We address the following specific aims to investigate this hypothesis. SPECIFIC AIM 1: Which cell types, somatic and spermatogenic germ cell stages, in the testes express the Arylhydrocarbon Receptor? SPECIFIC AIM 2. Are protein and mRNA expression of GLUT8, GLUT9a and GLUT9b in the testes affected by exposure to TCDD? Is the location of the transporters altered? SPECIFIC AIM 3: Does a lack of AhR expression eliminate the effect of TCDD in the testes? Does AhR deficiency affect glucose transporter expression in the testes? ! The rationale for this proposal is that identifying the mechanism of toxic injury to male germ cells will lead to a better understanding the role of environmental toxins in paternal transmission of malformations and male infertility. If successful in completing these aims, we will have elucidated a novel major downstream effect of activation of the Aryl hydrocarbon receptor. Exogenous activation of the AhR by dioxins, resulting in decrease glucose utilization among cells in the testes would highlight a likely mechanism of action that could further our understanding of certain reproductive outcomes that have been linked to paternal toxic exposures. ! ! PUBLIC HEALTH RELEVANCE: Dioxins represent a class of highly toxic and widely dispersed environmental hazards that are the unintentional byproducts of many industrial processes. Sperm cell production is known to be adversely affected by dioxin exposure, perhaps contributing to low sperm counts and poor function of the sperm cells. This research will help us better understand how such environmental exposures may affect the male reproductive tract.
Funding Period: 2012-01-01 - 2013-07-15
more information: NIH RePORT

Detail Information

Research Grants30

  1. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  2. Human Exposure to Bisphenol A, Phthalates and Fertility, Pregnancy Outcomes
    Russ B Hauser; Fiscal Year: 2013
    ..abstract_text> ..
  3. Soluble adenylyl cyclase isoforms essential for male fertility
    Lonny R Levin; Fiscal Year: 2013
    ..The studies proposed here may reveal unique aspects to the regulation of sperm cAMP signal transduction which could define a new target for contraceptive intervention. ..
  4. 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. ..
  5. Genetic Basis of Oligozoospermia in Infertile Males
    Alexander N Yatsenko; Fiscal Year: 2013
    ..The long-term career goals of the applicant is to become an independent physician-scientist focused on studying genetic disorders that affect male reproductive system. ..
  6. 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. ..
  7. 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. ..
  8. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  9. Program Project: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA
    Patricia K Donahoe; Fiscal Year: 2013
    ..Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies. ..
  10. Epididymal PMCA4 Expression Functional Impact and Mechanism of Sperm Uptake
    PATRICIA ANASTASIA DELEON; Fiscal Year: 2013
    ....
  11. Lineage tracing of germline stem cell differentiation in adult ovaries
    Ning Wang; Fiscal Year: 2013
    ....
  12. Do we need Y chromosome for successful reproduction?
    Monika A Ward; Fiscal Year: 2013
    ..Our results should translate to enhance treatment of human infertility associated with Y chromosome deletions. ! ..
  13. 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. ..
  14. Center for the Study of Reproductive Biology and Women's Health
    Jeffrey W Pollard; Fiscal Year: 2013
    ..He holds several senior administrative appointments in the College of Medicine and is well able to administer the proposed SCCPIR internally and to enable effective interactions with other SCCPIRs. ..
  15. MRNA PROCESSING IN REPRODUCTION AND FERTILIZATION
    Clinton C MacDonald; Fiscal Year: 2013
    ..Using a variety of techniques, we want to learn the molecular causes of why sperm production fails in males missing the CSTF2T gene, to better understand how to assist these infertile couples. ..
  16. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  17. Developing Male Contraceptives by Targeting ANT4
    Naohiro Terada; Fiscal Year: 2013
    ..PUBLIC RELEVANCE: This study has the potential to identify lead compounds and to ultimately develop novel male contraceptives that selectively eliminate male meiotic spermatocytes without damaging other cell types in the body. ..
  18. AMERICAN SOCIETY OF ANDROLOGY ANNUAL MEETING
    DONNA LEE VOGEL; Fiscal Year: 2013
    ..abstract_text> ..
  19. Origins and Biological Consequences of Human Infertility
    Linda C Giudice; Fiscal Year: 2013
    ..abstract_text> ..
  20. The evolutionary and molecular mechanisms underlying sperm performance in an emer
    Heidi S Fisher; Fiscal Year: 2013
    ....
  21. Adult and Transgenerational Toxicity Due to Developmental TCDD Exposure
    Tracie R Baker; Fiscal Year: 2013
    ..The University of Wisconsin has numerous NIH-sponsored training programs, core facilities and funded researchers making it an ideal training environment for me to develop as an independent scientist. ..
  22. RNA Editing in the Neonatal and Adult Testis
    Elizabeth M Snyder; Fiscal Year: 2013
    ..The knowledge gained from these studies represents a substantial contribution to the fields of male reproduction and RNA editing and may provide insight into the mechanisms of idiopathic male infertility. ..
  23. The MRAD9 Radioresistance Gene
    Howard B Lieberman; Fiscal Year: 2013
    ..abstract_text> ..
  24. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  25. Penn Center for Study of Epigenetics in Reproduction
    Marisa S Bartolomei; Fiscal Year: 2013
    ..abstract_text> ..
  26. Paternal Environmental Exposures and Reproductive Outcomes: A Comparison of in Vi
    DEBORAH ANN HANSEN; Fiscal Year: 2013
    ..In vivo and in vitro parameters include: a) 14.5 dpc placental and fetal weights, and crown to rump lengths;b) full term litter size, birth weights, and 5 week growth rates;and c) gross and microscopic structure. ..