Abstract
In rodents, in utero exposure to exogenous estrogens including diethylstilboestrol (DES) results in major suppression of steroidogenesis in fetal testes. Whether similar effects occur in the human fetal testis is equivocal. Based on the results of the rodent studies, we hypothesised that exposure of human fetal testes to DES would result in a reduction in testosterone production. We show, using a xenograft approach, that testosterone production is not reduced in human fetal testis following DES exposure. Human fetal testes (15–19 weeks’ gestation, n = 6) were xenografted into castrate male nude mice which were then treated for 35 days with vehicle or 100 µg/kg DES three times a week. For comparison, similar treatment was applied to pregnant rats from e13.5–e20.5 and effects on fetal testes evaluated at e21.5. Xenograft testosterone production was assessed by measuring host seminal vesicle (SV) weights as an indirect measure over the entire grafting period, and single measurement of serum testosterone at termination. Human fetal testis xenografts showed similar survival in DES and vehicle-exposed hosts. SV weight (44.3 v 26.6 mg, p = 0.01) was significantly increased in DES compared to vehicle-exposed hosts, respectively, indicating an overall increase in xenograft testosterone production over the grafting period, whilst serum testosterone at termination was unchanged. In contrast intra-testicular testosterone levels were reduced by 89%, in fetal rats exposed to DES. In rats, DES effects are mediated via Estrogen Receptor α (ESR1). We determined ESR1 protein and mRNA expression in human and rat fetal testis. ESR1 was expressed in rat, but not in human, fetal Leydig cells. We conclude that human fetal testis exposure to DES does not impair testosterone production as it does in rats, probably because ESR1 is not expressed in human fetal Leydig cells. This indicates that DES exposure is likely to pose minimal risk to masculinization of the human fetus.
Highlights
Male reproductive disorders are common and some have increased significantly in incidence in recent decades, raising concern about the role that lifestyle/environmental factors play in their etiology [1]
To determine the effect of exposure to DES on testosterone production from the xenografts, serum testosterone and seminal vesicle weight were measured in the host animals
In order to ensure that these results were due to effects on the xenografts and not the host animal, we measured seminal vesicle weight and serum testosterone in ungrafted mice
Summary
Male reproductive disorders (cryptorchidism, hypospadias, testicular germ cell cancer, low sperm counts) are common and some have increased significantly in incidence in recent decades, raising concern about the role that lifestyle/environmental factors play in their etiology [1]. Suppression of testosterone production resulting in abnormal testis development/function during fetal life has been implicated in the development of the TDS disorders [1,3,4,5]. Twenty years ago the so-called ‘estrogen hypothesis’ was proposed which suggested that the increasing incidence of reproductive abnormalities in the human male may be related to increased estrogen exposure in [6]. This hypothesis was supported by a number of studies in pregnant rats exposed to the synthetic estrogen DES and by some epidemiological data in male offspring of mothers exposed in utero to DES [2]. Studies in estrogen receptor-1 knockout (ERKO) mice have shown that the effects of DES are mostly mediated through classical estrogen signalling pathways involving ESR1 [9]
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