Maternal Exposure to a Low Dose of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Suppressed the Development of Reproductive Organs of Male Rats: Dose-Dependent Increase of mRNA Levels of 5 -Reductase Type 2 in Contrast to Decrease of Androgen Receptor in the Pubertal Ventral Prostate

Abstract

To assess the health risks associated with exposure to 2,3,7,8-tetrachlorodebenzo-p-dioxin (TCDD), we studied the effects of a relatively low dose of TCDD on the male reproductive system of rats, using the experimental protocol of T. A. Mably et al. (1992, Toxicol. Appl. Pharmacol. 114, 97-107, 108-117, 118-126), and searched for the most sensitive and reliable among several indices of TCDD toxicity. Pregnant Holtzman rats were given a single oral dose of 0, 12.5, 50, 200, or 800 ng TCDD/kg body weight on gestational day (GD) 15, and male offspring were sacrificed on postnatal day (PND) 49 or 120. GC-MS analysis of the abdominal fat tissue and testis clearly showed increased amounts of TCDD in these offspring. However, there was no TCDD effect on body weight of offspring. There were no changes on testicular or epididymal weights by TCDD administration, even at the 800-ng/kg dose in rats sacrificed on either PND 49 or 120. In addition, TCDD administration resulted in no changes in daily sperm production or sperm reserve at any of the doses used. However, the weight of the urogenital complex, including the ventral prostate, was significantly reduced at doses of 200 and 800 ng TCDD/kg in rats sacrificed on PND 120. Moreover, the anogenital distance (AGD) of male rats sacrificed on PND 120 showed a significant decrease in the groups receiving doses greater than 50 ng TCDD/kg. TCDD administration resulted in no apparent dose-dependent changes in levels of either serum testosterone or luteinizing hormone. Interestingly, reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that, in the ventral prostates of the PND 49 group, TCDD administration resulted in both a dose-dependent increase in 5alpha-reductase type 2 (5alphaR-II) mRNA level and a dose-dependent decrease in androgen receptor (AR) mRNA level. These results suggest that low-dose TCDD administration had a greater effect on the development of the external genital organs and ventral prostate than on development of the testis and other internal genital organs. Moreover, it is highly suggested that the decrease in the size of the ventral prostate by maternal TCDD exposure might be due to decreased responsiveness of the prostate to androgen due to an insufficient expression level of androgen receptor during puberty.

Developmental Neurotoxicity of Dioxin and Its Related Compounds.

“…Ohsako et al (2001) extensively examined the effects of TCDD on all male reproductive organs, and reported that the most conspicuous effects of TCDD were observed in the shortening of anogenital distance (AGD) and the decrease in ventral prostate weight with no effects on testes, and that the increase in 5α-reductase II mRNA and the decrease in androgen receptor mRNA were observed specifically in the ventral prostate 18) . Because this effect on male reproductive organs does not involve a significant difference in plasma testosterone and LH contents, and because a significant effect was observed even in very low-dose exposure (50 ng/kg given to dams on GD 15) 18) , which suggests the notion that low levels of TCDD affect particularly the reproductive organ, rather than an effect on the hypothalamo-pituitary axis, and that the development of the ventral prostate and the external genitalia is very susceptible to TCDD. Additionally, it is indicated that there is a critical window in the late fetal stage because these effects did not occur when a considerable amount of TCDD was administered at GD18 and PND2 (1 µg/kg to dams by gavage to dams and i.p.…”

Identification of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible and -suppressive Genes in the Rat Placenta: Induction of Interferon-regulated Genes with Possible Inhibitory Roles for Angiogenesis in the Placenta

“…Exposure to TCDD causes a diverse spectrum of toxicities in humans and laboratory animals [1][2][3][4]. The fetus is one of the most sensitive targets of TCDD and exhibits a wide range of biological responses at low TCDD levels that have no detectable effects on maternal side (usually the levels were ten to hundred times lower than those of LD50).…”

A Novel Spermatogenesis Related Factor-2 (SRF-2) Gene Expression Affected by TCDD Treatment

“…In the experiment of Ohsako et al TCDD was administered to mother rats at the gestational day 15 with the dose of 800 ng/kg at most. They observed no difference in body weight between control and 800 ng/kg dose group at postnatal day 120, but the expression of 5a reductase type 2 and androgen receptor gene was changed by TCDD treatment in the ventral prostates of the postnatal day 49 group [30]. In our experiment, a higher dose of TCDD was administered into rats repeatedly, and it is postulated that the endocrine system of these rats were greatly affected by the TCDD administration.…”

“…In some of these experiments, TCDD was administered to the mother rats at day 15 of gestation with the dose at most of 1,000 ng/kg, and the phenotypes of the offspring male rats were observed. They observed a decreased body weight and epididymal sperm reserves, and ejaculated sperm numbers [27][28][29], in contrast to another group's report, which observed no change of testicular weight or sperm production [30]. In the study of Faqi et al, the experimental procedure was similar to ours [14], because TCDD was administered during lactation.…”