"Testicular Dysgenesis Syndrome" has been proposed to explain the reported increase in the prevalence of human male reproductive tract abnormalities during the past half century. According to this hypothesis, the observed abnormalities-including malformed external genitalia (hypospadias), undescended testis (cryptorchidism), spermatogenic defects, and testis germ cell cancer-result from alterations in the in utero and perinatal hormonal milieu causing disruption of sensitive male reproductive tract developmental events. Attention has focused on environmental endocrine disrupting chemicals as possible causes of this developmental disruption. Phthalates are ubiquitous environmental contaminants and endocrine disrupting chemicals. Rats exposed to di-(n-butyl)phthalate) (DBP) during a critical in utero window of male reproductive tract development have decreased fetal testicular testosterone secretion, altered gene expression (including decreased steroidogenic gene expression), and many of the reproductive tract abnormalities associated with testicular dysgenesis syndrome. Surprisingly, in recent work conducted in our laboratories, we have discovered that, unlike the rat, fetal mouse testes are resistant to the testosterone and steroidogenic enzyme inhibitory effects of DBP. This observation of species specificity in the testicular dysgenesis response raises two important questions addressed by this application: What are the molecular pathway determinants of an effect of endocrine active toxicants on fetal testicular steroidogenesis? And what is the human fetal testicular response to endocrine disrupting chemicals, including DBP? In this project, a xenograft bioassay of fetal testes transplanted into a rodent host is optimized, considering host hormonal status, exposure parameters, and intrinsic testicular versus host susceptibility. The dose response of rat, mouse, and human fetal testis xenografts to model endocrine active toxicants (diethylstilbestrol [DES] and DBP) will then be determined. Using molecular analyses, gene profiling, and modeling, the comparative biology of the fetal testicular response to these endocrine disruptors will be explored, identifying biomarkers of susceptibility. These goals will be pursued with the following working hypothesis as a guide: Exposure of a xenotransplant bioassay predicts human fetal testicular susceptibility to endocrine active toxicants.

Public Health Relevance

Increases in human male reproductive tract abnormalities (falling sperm counts, hypospadias, cryptorchidism, and testis germ cell cancer) have been blamed on environmental exposures that alter the in utero and perinatal hormonal milieu. This project will develop a xenograft bioassay consisting of fetal testes implanted in a rodent host to directly assess human susceptibility to endocrine disrupting chemicals, including the plasticizer di-n-butyl phthalate.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017272-05
Application #
8586887
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Schug, Thaddeus
Project Start
2010-01-14
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$464,678
Indirect Cost
$156,137
Name
Brown University
Department
Pathology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Spade, Daniel J; Hall, Susan J; Saffarini, Camelia M et al. (2014) Differential response to abiraterone acetate and di-n-butyl phthalate in an androgen-sensitive human fetal testis xenograft bioassay. Toxicol Sci 138:148-60
Heger, Nicholas E; Hall, Susan J; Sandrof, Moses A et al. (2012) Human fetal testis xenografts are resistant to phthalate-induced endocrine disruption. Environ Health Perspect 120:1137-43