Developmental stage-specific effects of perinatal 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on reproductive organs of male rat offspring

Exposure to a relatively low dose of 2,3,7,8-tetrachlorodebenzo-p-dioxin (TCDD) during mid-gestation induces a reduction of ventral prostate weight in rat offspring. Recently we reported that a single administration of TCDD (12.5-800 ng/kg body weight) to pregnant Holtzman rats on gestational day (GD) 15 caused a decrease in androgen receptor (AR) mRNA level in the ventral prostate during the prepubertal period, and we proposed that this reduction of AR mRNA is one of the most sensitive adverse endpoints due to perinatal exposure to TCDD (S. Ohsako et al, 2001, Toxicol. Sci. 60, 132-143). In the present study, to investigate the mechanism of a decrease in AR mRNA level, we administered TCDD to rats at other developmental stages and compared possible alterations of the male reproductive system. Pregnant Sprague-Dawley rats were given a single oral dose of 1 mug TCDD/kg body weight on GD 15 or GD 18, or male pups born from untreated dams were subcutaneously given a single dose of 1 jig TCDD/kg body weight on postnatal day 2 (PND 2). Offspring exposed on GD 15, GD 18, and PND 2 were sacrificed on PND 70. TCDD exposure on GD 15 resulted in significant decreases in the urogenital complex and ventral prostate weights and urogenital-glans penis length of male rat offspring, but not on GD 18 and PND 2. Testicular and epididymal weights were also lower than control group only in the TCDD-exposed GD 15 group. Anogenital distance was significantly reduced in the TCDD-exposed GD 15 and GD 18 groups, but not in the TCDD-exposed PND 2 group. Semiquantitative RT-PCR analysis showed that AR mRNA levels were decreased in the TCDD-exposed GD 15 group only, and that the constitutive level of cytochrome P450 1A1 (CYP1A1) mRNA in the ventral prostate was not changed by TCDD in any of the exposed groups. No changes in AR mRNA level were detected in the testis or brain in any of the TCDD-exposed groups. These results suggest the presence of a critical window during development with regard to impairments of male reproductive organs by in utero and lactational exposure to a low dose of TCDD.