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Submitted on June 6, 2005
Accepted on July 12, 2005
Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The University of Edinburgh Academic Centre, Edinburgh EH16 4SB, UK; School of Molecular and Biomedical Sciences, University of Adelaide, SA 5005 Adelaide, Australia; GERM-INSERM U625, Campus de Beaulieu, Université de Rennes 1, 35042 Rennes Cedex, Bretagne, France; Institute for Immunology, University Hospital Hamburg-Eppendorf, Martinistra
e 52, D-20246 Hamburg, Germany; Department of Andrology, University Hospital Hamburg-Eppendorf, Martinistrae 52, D-20246 Hamburg, Germany
* To whom correspondence should be addressed. E-mail: r.sharpe{at}hrsu.mrc.ac.uk.
Cryptorchidism is a common reproductive abnormality, possibly resulting from abnormal hormone production/action by the fetal testis. Insulin-like factor 3 (Insl3) is thought to be involved in gubernaculum development and transabdominal testicular descent, but its importance is unclear, due partly to lack of suitable Insl3 antibodies. We have generated (by genetic immunization) and validated a novel antirat Insl3 antibody, which we used to characterize immunoexpression of Insl3 in rat Leydig cells (LC) from fetal life until adulthood, and its relationship to cryptorchidism. Immunoexpression was strong on embryonic day 17.5 (E17.5) and E19.5, and from 35 days of age onwards, but weak from E21.5 until puberty. Since in utero exposure to di (n-butyl) phthalate (DBP) induces cryptorchidism and suppresses Insl3 gene expression, we investigated Insl3 protein expression in fetal and adult rats exposed to 500 mg/kg/day DBP from E13.5-E21.5. Expression on E17.5 and E19.5 decreased dramatically following DBP exposure, but there was no consistent correlation between this suppression and abnormal testis position. We also compared expression of Insl3 and P450 side-chain cleavage enzyme (P450scc) in fetal testes from rats exposed in utero to DBP or to flutamide (50 mg/kg/day). DBP treatment suppressed expression of both P450scc and Insl3 at E19.5, but flutamide exposure had no effect on either protein, demonstrating that Insl3 expression in fetal rat LC is not androgen-regulated. In adult rats, Insl3 expression was suppressed in 80% of cryptorchid and 50% of scrotal testes from rats exposed to DBP, suggesting that prenatal DBP exposure also leads to maldevelopment/malfunction of the adult LC population in some animals.
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