2007 Study Abstract
There are numerous reports indicating that estrogenic molecules affect testicular descent both in rodents and humans. In fact, before the identification of Insl3 and LGR8 mutant mice, the main model for intraabdominal cryptorchidism involved the exposure of pregnant rodents to exogenous estradiol (E2).
In humans, the offspring of pregnant women treated with diethylstilbestrol (DES), a nonsteroidal estrogenic substance used during the 1950s to 1970s to prevent miscarriages, exhibited an increased incidence of cryptorchidism and hypoplastic testes. In rodents, we and others have shown that administration of DES or E2 during the second half of gestation resulted in a drastic reduction of Insl3 gene expression and testosterone levels, even though the expression of Sf-1 was unaltered. Recently, it has been shown that exposure to mono-N-butyl phthalate, an endocrine disruptor with weak estrogenic activities, also impairs Insl3 gene expression and testicular descent in rat embryos.
Collectively, these reports indicate that xenoestrogen-dependent cryptorchidism is caused by a down-regulation of Insl3 gene expression. However, the molecular mechanisms mediating estrogen-dependent inhibition of fetal Leydig cell function and cryptorchidism remain an important open question. The purpose of this study was to investigate the toxicogenomic effects of DES or E2 exposure on testicular gene expression, and to assess the contribution of the estrogen receptors (ERs) α or β in mediating these effects with an emphasis on Insl3 gene expression and testicular descent. We found 63 and 175 genes that were respectively down- or up-regulated by estrogen exposure in fetal testes; for more than half of these, this was mediated by ERα. The expression of Leydig-specific genes such as Insl3, cytochrome P450 17α-hydroxylase/17,20-lyase (Cyp17a1), steroidogenic acute regulatory protein (Star), and renin 1 (Ren1) was profoundly decreased upon exposure to E2 or DES but not affected in mutant testes lacking ERα. These data suggest that estrogenic exposure affects fetal Leydig cell endocrine functions, more precisely the steroidogenic function, Insl3 expression and testicular descent, via an ERα-dependent mechanism.
Sources
- Full study (free access) : Estrogen Receptor α Is a Major Contributor to Estrogen-Mediated Fetal Testis Dysgenesis and Cryptorchidism, Endocrinology, Oxford University Press, doi.org/10.1210/en.2007-0689, 01 November 2007.
DES DIETHYLSTILBESTROL RESOURCES
- Source DES and cryptorchidism studies, DES and hypospadias studies.
- Diethylstilbestrol DES studies listed by topics and date of publication.