ToxSci Advance Access originally published online on May 11, 2005
Toxicological Sciences 2005 86(2):387-395; doi:10.1093/toxsci/kfi189
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In Utero and Lactational 2,3,7,8-Tetrachlorodibenzo-p-dioxin Exposure: Effects on the Prostate and Its Response to Castration in Senescent C57BL/6J Mice
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* School of Pharmacy and Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53705; and Department of Veterinary Biosciences, University of Illinois, Urbana, Illinois 61802
Received February 1, 2005; accepted April 21, 2005
In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure inhibits ventral, dorsolateral, and anterior prostate development in C57BL/6 mice. To determine if prostatic abnormalities persist into senescence, mice born to dams given TCDD (5 µg/kg, po) or vehicle on gestation day 13 were examined at 100 and 510 days of age. Half the mice were castrated ten days prior to necropsy in order to assess androgen dependence, while the remaining mice were sham castrated. Effects of TCDD on the dorsolateral and anterior prostate of senescent sham-castrated mice were relatively subtle, whereas the ventral prostate was rudimentary or absent. Castration of vehicle-exposed mice caused far greater reductions in prostate lobe weights, epithelial cell height, and androgen-dependent gene expression (MP25 and probasin) in young mice than in senescent ones, while cell proliferation was decreased by castration in young mice and increased in senescence. Responses to castration were similar at 100 days of age in vehicle- and TCDD-exposed mice. At 510 days, however, TCDD-exposed mice were substantially more responsive to castration by most indices than vehicle-exposed mice. These results demonstrate that prostatic androgen dependence in mice declines substantially with age in several key ways, and that in utero and lactational TCDD exposure protects against this decline. Surprisingly, TCDD increased the incidence of cribriform structures in dorsolateral prostate ducts, from 2–3% in vehicle-exposed senescent mice to 16% in sham-castrated and to 7% in castrated senescent mice. Collectively, these results demonstrate that effects of in utero and lactational TCDD exposure on the prostate persist into senescence, and suggest that in utero and lactational TCDD exposure retards the aging process in the prostate. However, because cribriform structures are often considered to be associated with prostate carcinogenesis, these results also suggest that TCDD exposure early in development may increase susceptibility to prostate cancer.
Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; prostate; senescence; castration; cribriform structures; C57BL/6J mouse.
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