2001 Progress Report: Endocrine Disruptors and Testis DevelopmentEPA Grant Number: R827405
Title: Endocrine Disruptors and Testis Development
Investigators: Skinner, Michael K.
Institution: Washington State University
EPA Project Officer: Fields, Nigel
Project Period: August 1, 1999 through July 31, 2002
Project Period Covered by this Report: August 1, 2000 through July 31, 2001
Project Amount: $534,583
RFA: Endocrine Disruptors (1999) RFA Text | Recipients Lists
Research Category: Economics and Decision Sciences , Endocrine Disruptors , Health , Safer Chemicals
Objective:The proposed research is designed to develop a better understanding of how endocrine disruptors influence testis development and function. Of particular interest are the cell-cell interactions that regulate testis growth, size, and morphogenesis that directly influence male fertility and sperm production. Sertoli cells are the epithelial cells responsible for the onset of embryonic testis development and maintenance of spermatogenesis in the adult testis. Preliminary research has demonstrated that two families of paracrine growth factors directly influence testis development and function. The hypothesis tested is that endocrine disruptors affect locally produced paracrine growth factors, which are essential for testicular cell growth and differentiation during embryonic and postnatal testis development and that this directly influences male fertility and sperm production in the adult. Abnormal testis development and male infertility caused by endocrine disruptors may in part be due to inappropriate control of testicular cell growth and differentiation during development. Preliminary studies indicate that the transforming growth factor families are critical for the embryonic testis growth. Preliminary studies also indicate that the neurotropin family of factors (i.e., NT3) has a critical role in the morphogenesis of testis development (i.e., sex cord or seminiferous tubule formation). The experimental approach consists of the following specific aims:
1. Investigate the effects of endocrine disruptors on the transforming growth factor families during testis development.
2. Investigate the effects of endocrine disruptors on the neurotropin growth factor family during testis development.
3. Investigate the physiological effects of these endocrine disruptors during testis development on male fertility.
The completion of these studies will provide insight into the mechanisms that endocrine disruptors influence testis growth and function. Testicular cell growth and differentiation is essential for embryonic, prepubertal, pubertal, and adult testis function. Abnormal control of critical cell-cell interactions after treatment with endocrine disruptors is anticipated to result in male infertility. Inappropriate expression of the growth factors or receptors will result in subfertile males. Therefore, observations from the current project will provide an understanding of the actions of endocrine disruptors on testis development and function. Information obtained will determine how environmental toxins with estrogenic (e.g., methoxychlor) and anti-androgenic (e.g., vinclozoline) activities may impair male fertility by adversely effecting gonadal neurotropins and transforming growth factors.
Progress Summary:Progress on each of the specific aims is summarized below:
1. The methods developed to assess the transforming growth factor gene expression and protein expression have been utilized, along with the embryonic testis organ culture system developed to examine the effects of methoxychlor on TGF mRNA levels. Methoxychlor as little as 0.2 M suppresses TGF and EGF receptor mRNA levels. This is now being more thoroughly investigated. Currently, the TGF isoforms also are being investigated. The actions of methoxychlor and its metabolite HPTE on testis development has been established as shown in the publications below.
2. The methods developed to assess neurotropin gene expression has been utilized to examine the actions of methoxychlor (MXC). MXC was found to suppress NT3 and trkC mRNA levels. This correlated with the ability of methoxychlor to block cord formation in the developing testis. This is now being investigated more thoroughly and other neurotropins are being assessed.
3. In vivo experiments with exposure of gestating mothers to methoxychlor demonstrated effects on the F1 generation. A reduction in sperm function and increased spermatogenic cell apoptosis was demonstrated. Preliminary observations that this effect may be transgenerational are now being investigated.
The following future activites will be conducted:
Aim 1: Complete analysis of effects on TGF , TGF 1, TGF 2, and TGF 3
relevant receptors. Correlate with morphologic and functional changes in embryonic testis development.
Aim 2: Complete analysis of effects on all the neurotropins and receptors.
Aim 3: Extend analysis to F1, F2, and F3 generations. Also, assess epigenetic effects on germ-line population through methylation studies.
Journal Articles on this Report : 4 Displayed | Download in RIS Format
|Other project views:||All 16 publications||12 publications in selected types||All 12 journal articles|
||Cupp AS, Skinner MK. Actions of the endocrine disrupter methoxychlor and its estrogenic metabolite on in vitro embryonic rat seminiferous cord formation and perinatal testis growth. Reproductive Toxicology 2001;15(3):317-326||
||Cupp AS, Uzumcu M, Suzuki H, Dirks H, Phillips B, Skinner MK. Effect of transient embryonic in vivo exposure to the endocrine disruptor methoxychlor on embryonic and postnatal testis development. Journal of Andrology 2003;24(5):736-745.||
||Levine E, Cupp AS, Skinner MK. Role of neurotropins in rat embryonic testis morphogenesis (cord formation). Biology of Reproduction 2000;62(1):132-142.||
||Levine E, Cupp AS, Miyashiro L, Skinner MK. Role of transforming growth factor-α and the epidermal growth factor receptor in embryonic rat testis development. Biology of Reproduction 2000;62(3):477-490||
Supplemental Keywords:methoxychlor, environment exposure, testis biology, in vivo and in vitro testing, endocrine disruptors, reproductive toxicology, environmental biology., RFA, Health, Scientific Discipline, Geographic Area, Health Risk Assessment, Endocrine Disruptors - Environmental Exposure & Risk, endocrine disruptors, Risk Assessments, Biochemistry, Children's Health, Molecular Biology/Genetics, Biology, Endocrine Disruptors - Human Health, EPA Region, neurotropin growth, cell-cell interactions, testis development, EDCs, endocrine disrupting chemicals, sexual development, sertoli cells, developmental biology, human exposure, human growth and development, physiology, fetal development, chemical interference, embryonic development, Region 10, gonad morphology, postnatal development, paracine growth factors
Progress and Final Reports:Original Abstract
2000 Progress Report
2002 Progress Report