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.
Species-Specific Dibutyl Phthalate Fetal Testis Endocrine Disruption Correlates with Inhibition of SREBP2-Dependent Gene Expression Pathways
