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

Abstract

Common male reproductive abnormalities including cryptorchidism, hypospadias, and low sperm counts may comprise a testicular dysgenesis syndrome (TDS), resulting from fetal testis dysfunction during a critical developmental period involving reduced androgen production/action. The recent increase in TDS prevalence suggests environmental/lifestyle factors may be etiologically important. The developing fetus is exposed to multimodal challenges, and we hypothesized that exposure to a combination of factors rather than single agents may be important in the pathogenesis of TDS. We experimentally induced fetal testis dysfunction in rats via treatment of pregnant females daily from embryonic day (e) 13.5 to e21.5 with vehicle, 100 or 500 mg/kg . d dibutyl phthalate (DBP), 0.1 mg/kg . d dexamethasone (Dex), or a combination of DBP + Dex. In adulthood, penile length/normality, testis weight/descent, prostate weight, and plasma testosterone levels were measured plus anogenital distance (AGD) as a measure of androgen action within the masculinization programming window. Intratesticular testosterone and steroidogenic enzyme gene expression were measured in fetal testes at e17.5. High-dose DBP reduced fetal intratesticular testosterone and steroidogenic gene expression; induced mild hypospadias (31%) and cryptorchidism (53%); and reduced penile length, AGD, and testis and prostate weight in adulthood. Dex alone had no effect except to reduce birth weight but amplified the adverse effects of 500 mg/kg . d DBP and exacerbated the effects of 100 mg/kg . d DBP. All adverse effects were highly correlated to AGD, emphasizing the etiological importance of the masculinization programming window. These findings suggest that exposure to common environmental chemicals in combination with, for example, maternal stress, may increase the risk of common male reproductive abnormalities, with implications for human populations.

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

“…There is also evidence from human (13,14) and animal experimental (15) studies that fetal programming can influence adult testosterone levels, particularly that reduced fetal androgen exposure leads to lower adult male testosterone levels (14,15). This data fits with growing evidence that subtle deficiency in fetal androgens is a major determinant of adult male reproductive disorders, such as low sperm production (16,17), and might explain why low sperm counts are often associated with compensated Leydig cell failure in men (18).…”

“…There is a similar connection between reduced fetal androgens and reduced adult sperm counts/sperm production in men and rats (15,16). What further ties these observations together is that men with low sperm counts commonly exhibit compensated adult Leydig cell failure, although why is unknown (18,60,67).…”

The effects on steroidogenesis and histopathology of adult male Japanese quails (Coturnix coturnix japonica) testis following pre-pubertal exposure to di(n-butyl) phthalate (DBP)

“…In addition, exposure to dexamethasone exacerbated 500 mg/kg DBP-mediated reduction in adult testicular weight and resulted in reduced testicular weight when given in combination with 100 mg DBP, compared with controls. Overall, these effects paralleled the reductions in plasma testosterone levels of DBP treated rats (Drake et al, 2009). Furthermore, immature male rat treated daily with di-(2 ethylhexyl) phthalate (DEHP) and flutamide (Flu) on postnatal days (PNDs) 21 to 35 showed significant decreases in the weights of the testes, prostate, and seminal vesicle and anogenital distances (AGD) in response to high DEHP dose (500 mg/kg body mass) or Flu (50 mg/ kg body mass) (Vo et al, 2009).…”

“…Otherwise, our observation is in accordance with the of study of Brunström et al (2009), showing that plasma testosterone concentration was not affected when Quail embryos were exposed to EDCs, suggesting that the observed impeded growth was not due to insufficient testosterone levels. Elsewhere, it was reported that fetal exposure of rats to DBP at 100 mg/kg or dexamethasone (0.1 mg/kg) alone had no effects on testis weight, ventral prostate weight, or penis length, whereas 500 mg DBP/kg significantly reduced these parameters (Drake et al, 2009). In addition, exposure to dexamethasone exacerbated 500 mg/kg DBP-mediated reduction in adult testicular weight and resulted in reduced testicular weight when given in combination with 100 mg DBP, compared with controls.…”

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

“…The MPW refers to the window of time during fetal development in which androgen actions program later development of all male reproductive organs, including their ultimate adult size and function (20)(21)(22). A vital finding was that anogenital distance (AGD), which is normally about twice as long in rodent males as in females, was also programmed by androgen action within the MPW (20,23).…”