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Studies on rodents have prompted the notion that a syndrome exists in the human male which includes phenotypic alterations such as hypospadias, cryptorchidism, poor semen quality, and even testicular cancer. Each phenotype in this \u2018testicular dysgenesis syndrome\u2019 is predicated on reduction in testosterone production by the fetal Leydig cell. We sought to examine the relationship between dysgenesis and steroidogenic capacity in the fetal rat testis more stringently by incorporating lower exposures than those typically used, conducting a comprehensive, non-targeted quantitative evaluation of the fetal testis proteome, and relating alterations in individual proteins to the capacity of the fetal Leydig cell to produce testosterone, and histopathology of the fetal testis. Pregnant dams were dosed orally from gestation day (GD) 13\u201319 with 0, 10, or 100\u200amg diethylhexyl phthalate (DEHP)\/kg body weight per day. Each endpoint was represented by 16\u200al. Clustering of Leydig cells occurred before any significant decrease in the capacity of the GD19 Leydig cell to produce testosterone. At 100\u200amg DEHP\/kg, testosterone production was reduced significantly, Leydig cell clusters became quite large, and additional dysgenetic changes were observed in the fetal testis. Of 23 proteins whose expression was altered significantly at both DEHP exposure levels, seven were found to be correlated with and predictive of the quantified endpoints. None of these proteins have been previously implicated with DEHP exposure. Notably, pathway analysis revealed that these seven proteins fit a pathway network in which each is regulated directly or indirectly by estradiol.<\/jats:p>","DOI":"10.1530\/rep-12-0266","type":"journal-article","created":{"date-parts":[[2012,10,6]],"date-time":"2012-10-06T21:13:37Z","timestamp":1349558017000},"page":"747-761","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":46,"title":["Novel molecular targets associated with testicular dysgenesis induced by gestational exposure to diethylhexyl phthalate in the rat: a role for estradiol"],"prefix":"10.1093","volume":"144","author":[{"given":"Gary R","family":"Klinefelter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W","family":"Laskey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Witold M","family":"Winnik","sequence":"additional","affiliation":[{"name":"United States Environmental Protection Agency Office of Research and Development, Toxicology Assessment Division, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Branch, MD#72, Reproductive Toxicology Facility, Durham, North Carolina 27713, USA 1National Health and Environmental Effects Research Laboratory Proteomic Research Core, Durham, North Carolina 27711, USA 2Toxicology Assessment Division National Health and Environmental Effects Research Laboratory, Endocrine Toxicology Branch, MD#72, Reproductive Toxicology Facility, Durham, North Carolina 27713, USA and 3Animal Reproduction and Biotechnology Laboratory Colorado State University, Fort Collins, Colorado 80523-1683, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan D","family":"Suarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi L","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lillian F","family":"Strader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandy W","family":"Riffle","sequence":"additional","affiliation":[{"name":"United States Environmental Protection Agency Office of Research and Development, Toxicology Assessment Division, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Branch, MD#72, Reproductive Toxicology Facility, Durham, North Carolina 27713, USA 1National Health and Environmental Effects Research Laboratory Proteomic Research Core, Durham, North Carolina 27711, USA 2Toxicology Assessment Division National Health and Environmental Effects Research Laboratory, Endocrine Toxicology Branch, MD#72, Reproductive Toxicology Facility, Durham, North Carolina 27713, USA and 3Animal Reproduction and Biotechnology Laboratory Colorado State University, Fort Collins, Colorado 80523-1683, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D N Rao","family":"Veeramachaneni","sequence":"additional","affiliation":[{"name":"United States Environmental Protection Agency Office of Research and Development, Toxicology Assessment Division, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Branch, MD#72, Reproductive Toxicology Facility, Durham, North Carolina 27713, USA 1National Health and Environmental Effects Research Laboratory Proteomic Research Core, Durham, North Carolina 27711, USA 2Toxicology Assessment Division National Health and Environmental Effects Research Laboratory, Endocrine Toxicology Branch, MD#72, Reproductive Toxicology Facility, Durham, North Carolina 27713, USA and 3Animal Reproduction and Biotechnology Laboratory Colorado State University, Fort Collins, Colorado 80523-1683, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,12,1]]},"reference":[{"key":"2026010712583718900_bib1"},{"key":"2026010712583718900_bib2","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1073\/pnas.0305977101","article-title":"Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances","volume":"101","author":"Akingbemi","year":"2004","journal-title":"PNAS"},{"key":"2026010712583718900_bib3","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1093\/humrep\/dep174","article-title":"Does a testicular dysgenesis syndrome exist?","volume":"24","author":"Akre","year":"2009","journal-title":"Human Reproduction"},{"key":"2026010712583718900_bib4","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1021\/pr060206k","article-title":"Identification of 14-3-3 epsilon substrates from embryonic murine brain","volume":"5","author":"Ballif","year":"2006","journal-title":"Journal 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