An apparent increase in the prevalence of human male reproductive tract abnormalities during the past half century have led Skakkebaek to articulate """"""""testicular dysgenesis syndrome"""""""" as an explanation for this phenomenon. According to Skakkebaek, the observed abnormalities-including malformed external genitalia (hypospadias), undesecended testis (cryptorchidism), spermatogenic defects, and testis germ cell cancer- result from the alterations in the in utero and perinatal hormonal milieu causing disruption of sensitive male reproductive tract development events. Attention is 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 critical in utero window of male reproductive tract development have altered gene expression and a number of reproductive tract abnormalities associated with testicular dysgenesis syndrome, including underdeveloped or absent reproductive organs, hypospadias, cryptorchidism and decreased sperm production. Although testis germ cell cancer has not been observed in this rat model, the fetal testes of DBP-exposed male rats contain dysplastic, multinucleated gonocytes. ? ? In this project, a new mouse model of gestational DBP-induced testicular dysgenesis is established. After characterizing alterations in gene expression in this genetically tractable species, p53-deficient mice will be used to allow DBP-induced dysplastic gonocytes to persist in the postnatal testis rather than degenerate and die. We expect these persistent dysplastic gonocytes to become transformed in the p53-deficient environment, resulting in tumorigenesis and the development of testis germ cell cancer. These goals will be pursued with the following working hypothesis as a guide: Disruption of mammalian in utero hormonal environment by phthalates produces a common spectrum of abnormalities across species, including a predilection to testicular carcinogenesis unmasked in p53-deficient mice. ? ?
| 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 |
| Saffarini, Camelia M; Heger, Nicholas E; Yamasaki, Hideki et al. (2012) Induction and persistence of abnormal testicular germ cells following gestational exposure to di-(n-butyl) phthalate in p53-null mice. J Androl 33:505-13 |
| Boekelheide, Kim; Kleymenova, Elena; Liu, Kejun et al. (2009) Dose-dependent effects on cell proliferation, seminiferous tubules, and male germ cells in the fetal rat testis following exposure to di(n-butyl) phthalate. Microsc Res Tech 72:629-38 |
| Gaido, Kevin W; Hensley, Janan B; Liu, Delong et al. (2007) Fetal mouse phthalate exposure shows that Gonocyte multinucleation is not associated with decreased testicular testosterone. Toxicol Sci 97:491-503 |
