Toxicological Sciences 68, 479-487 (2002)
Copyright © 2002 by the Society of Toxicology
REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY |
Effects of Aryl Hydrocarbon Receptor Null Mutation and in Utero and Lactational 2,3,7,8-Tetrachlorodibenzo-p-dioxin Exposure on Prostate and Seminal Vesicle Development in C57BL/6 Mice
,
,¶,,2
* School of Pharmacy,
Endocrinology-Reproductive Physiology Program,
Environmental Toxicology Center, and
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin; and
¶ William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin
Experiments were conducted to determine the effects of aryl hydrocarbon receptor (AhR) null mutation and in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, alone and in combination, on prostate and seminal vesicle development in C57BL/6 mice. AhR heterozygous (Ahr+/-) mice were mated, and pregnant females were dosed orally on gestation day 13 with TCDD (5 µg/kg) or vehicle. Pups underwent necropsy on postnatal days (PNDs) 35 and 90. Comparison of vehicle-exposed AhR knockout (AhRKO;Ahr-/-) with wild-type (Ahr+/+) pups revealed that the AhR is necessary for normal dorsolateral prostate, anterior prostate, and seminal vesicle development but apparently not for ventral prostate development. In wild-type mice,in utero and lactational TCDD exposure reduced ventral prostate weight by 79–87% and mRNA expression for its major androgen-dependent secretory protein (MP25) by 99%. Yet high levels of mRNA for a secretory protein normally produced primarily by the lateral prostate (PSP94) were expressed. These effects were predominantly AhR dependent because TCDD had little if any effect in AhRKO mice. TCDD reduced dorsolateral prostate weight in wild-type but not AhRKO mice and had no significant effect on expression of mRNA for PSP94 or for probasin, a major androgen-dependent secretory protein. The PSP94 results suggest that TCDD may have caused a respecification of prostatic gene expression. TCDD reduced anterior prostate weight by more than half, and expression of mRNA for its major androgen-dependent secretory protein (renin-1) was greatly reduced. These effects were AhR dependent. Seminal vesicle weight was reduced by TCDD in wild-type mice but was increased in AhRKO mice on PND 35 and decreased on PND 90 (relative weight only). Androgen receptor mRNA levels were not significantly altered in any prostate lobe, and all organs appeared histologically normal in all groups. Serum testosterone concentrations were unchanged, and modest reductions in serum 5
-androstane-3,17ß-diol concentrations could not account for the effects on sex organs. Collectively, these results indicate that the AhR signaling pathway plays a role in normal accessory sex organ development and thatin utero and lactational TCDD exposure disrupts development of these organs via spatially and perhaps temporally specific mechanisms.
Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; in utero; lactational exposure; TCDD; aryl hydrocarbon receptor null mutation; AhRKO mice; prostate; seminal vesicles; gene expression; development; mice.
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