2000 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: Louie, Nica
Project Period: August 1, 1999 through July 31, 2002
Project Period Covered by this Report: August 1, 1999 through July 31, 2000
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 which 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 effect locally produced paracrine growth factors that are essential for testicular cell growth and differentiation during embryonic and potnatal 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; and (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 proposal 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:
- The methods to assess the transforming growth factor gene expression and protein expression have been established. Using the embryonic testis organ cultures the effects of methoxychlor on TGFa mRNA levels. Methoxychlor as little as 0.2 mM suppresses TGFa mRNA levels. This is now being more thoroughly investigated and TGFb isotopes are also being investigated. The actions of methoxychlor and its metabolite HPTE on testis development was also established.
- The methods to assess neurotropin gene expression and protein expressions were established. The actions of methoxychlor were found to suppress NT3 and trkC mRNA levels. This correlated with the ability of methoxychlor to block cord formation in the developing testis.
- 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.