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Human Fetal Testis Xenografts Are Resistant to Phthalate-Induced Endocrine Disruption

Nicholas E. Heger, Susan J. Hall, Moses A. Sandrof, Elizabeth V. McDonnell, Janan B. Hensley, Erin N. McDowell, Kayla A. Martin, Kevin W. Gaido, Kamin J. Johnson and Kim Boekelheide
Environmental Health Perspectives
Vol. 120, No. 8 (AUGUST 2012), pp. 1137-1143
Stable URL: http://www.jstor.org/stable/41553127
Page Count: 7
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Abstract

Background: In utero exposure to endocrine-disrupting chemicals may contribute to testicular dysgenesis syndrome (TDS), a proposed constellation of increasingly common maje reproductive tract abnormalities (including hypospadias, cryptorchidism, hypospermatogenesis, and testicular cancer). Male tats exposed in utero to causing TDS-consistent effects of hypospadiae and cryrrtorchidj rn. Mice exposed to in utero exhibit MNG induction only, This disparity in response demonstrates a species-specific sensitivity to phthalate-induced suppression of fetal Leydig cell sterotdogenesis. Impomntly, ex vivo phthalate exposure of the letal testis does not recapitulate the species-specific endocrine disruption, demonstrating me need for a new bioassay to assess the human response to phthalates. Objectives: In this study, we aimed to develop and validate a rat and mouse testis xenograft bio assay of phthalate exposure and examine tlie human fetal testis response. Methods: Fetal rat, mouse, and human testes were xenografted into immunodeficient rodent hosts, and hosts were gavaged with a range of phthalate doses over multiple days. Xenografts were harvested and assessed for histopathology and steroidogenic end points. Results: Consistent with the in utero response, phthalate exposure induced MNG formation in sat and mouse xenografts, but only rats exhibited suppressed steroidogenesis. Across a range of doses, human fetal testis xenografts exhibited MNG induction but were resistant to suppression of steroidogenic gene expression. Conclusions: Phthalate exposure of grafted human fetal testis altered fetal germ cells but did Hot reduce expression of genes that regulate fetal testosterone biosynthesis. :

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