Effects of Pre‐natal Glucocorticoids on Testicular Development in Sheep

Abstract

We tested the hypothesis that acute pre-natal exposure to high levels of synthetic glucocorticoid (betamethasone) would alter fetal testicular development through actions on gonadal glucocorticoid receptors (GRs). Pregnant Merino ewes bearing singleton male fetuses (n = 24) were allocated randomly among four equal groups to be injected intramuscularly with saline or betamethasone (0.5 mg/kg) either on day 109 of gestation or on both day 109 and day 116 of gestation. Fetal testes were collected at post-mortem, 5 days after each treatment. The volume of interstitial tissue and the volume, length and diameter of the sex cords were measured, and Sertoli cells and gonocytes were counted. For cord volume and interstitial tissue volume, control testes demonstrated maturational changes as fetal age advanced from 109 to 116 days of gestation. For that period, the single injection of betamethasone significantly reduced Leydig cell proliferation (P < 0.05), but had no effect on Sertoli cell numbers. Immunohistochemistry was used to localize GR and proliferating cell nuclear antigen in testicular cells. GR immunoexpression in Leydig cells was higher in fetuses exposed to betamethasone at 109 days of gestation than in control fetuses. Sertoli cells showed low levels of GR. It was concluded that, during mid-gestation, a brief period of glucocorticoid treatment could affect testicular development in male sheep fetuses. The mechanism probably involves direct effects on Leydig cells, as these cells express extra-GR in response to the treatment. Sertoli cells seem to produce less GR than Leydig cells, perhaps explaining their lack of response to betamethasone. These outcomes may have important implications for future fertility in male offspring.

Apoptosis‐Related Protein Expression During Pre‐ and Post‐Natal Testicular Development After Administration of Glucocorticoid in utero in the Sheep

“…We have previously shown that, in sheep, pre‐natal exposure to synthetic glucocorticoids reduces Leydig cell proliferation and increases the expression of glucocorticoid receptor in foetal testicular tissue (Pedrana et al. ). Given the role that glucocorticoids play in regulating apoptotic signalling pathways (Sasagawa et al.…”

Glucocorticoids Amplify Dibutyl Phthalate-Induced Disruption of Testosterone Production and Male Reproductive Development

“…This implies that stress or malnutrition (which attenuate the placental 11␤-HSD2 barrier to maternal glucocorticoids) in pregnancy may reveal TDS spectrum disorders in human populations exposed to numerous chemicals with antiandrogenic activity (32,33). How glucocorticoids amplify antiandrogenic effects in the fetal testis/reproductive tract remains to be determined, but fetal glucocorticoid exposure alters proliferation and function of the adult Leydig cell population (55,56), perhaps by down-regulating steroidogenic enzyme expression (57), key nodes in the effects of androgens on testicular development (58). Although recent reviews have suggested that there is an urgent need to consider the toxicological effects of pharmaceutical agents and endocrine-disrupting chemicals on the hypothalamic-pituitary-adrenal axis (17,59), this is the first study to report that interactions between glucocorticoids and environmental chemicals known to have an effect on reproductive development may play a causative role in increasing disease susceptibility.…”

Foetal exposure to Panax ginseng extract reverts the effects of prenatal dexamethasone in the synthesis of testosterone by Leydig cells of the adult rat

“…There is reference of an increase in GR expression in foetal Leydig cells from sheep exposed to betamethasone in utero (Pedrana et al . ). However, there are no previous data on postnatal GR expression in Leydig cells.…”