Prenatal Exposure to Flutamide Induces Increased Keratinocyte Growth Factor mRNA, Irreversible Alteration of the Ductal Architecture, but No Change in Receptor Binding Capacity in the Rat Prostate Later in Life

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Pregnant rats were administered flutamide at a daily dose of 10 mg/kg from gestation day 12 (GD12) to GD21, or 30 mg/kg on 2 successive days in the period from GD14 to 21 (GD14-15, GD16-17, GD18-19, and GD20-21). The effects on ventral prostate in male offspring were examined by RT-PCR on postnatal day 1 (PND1) for the 10 mg/kg group, and by receptor binding assay at PND76 or 78 and morphologically at PND7, 14, and 21 for all groups. RT-PCR demonstrated increase in mRNAs for the androgen receptor (AR) and the keratinocyte growth factor (KGF), but not transforming growth factor (TGF)-beta1 and beta2, the epidermal growth factor receptor (EGFR), and the vascular endothelial growth factor (VEGF). Prostate tissue showed a consistent reduction in the number of main ducts and ductal branchpoints, as well as the complexity of the terminal ductal network in the 10 mg/kg group, and the 30 mg/kg GD16-17 and GD18-19 groups. The effect on ductal architecture was severest with the 10 mg/kg regimen. The organ weights at PND76 or 78 were reduced in all flutamide treated groups. The value for the 10 mg/kg group was lowest, while the 30 mg/kg GD14-15 and GD20-21 groups were least affected. Receptor binding assays exhibited no significantly difference regarding maximum binding capacity (Bmax) and dissociation constant (Kd) between the control and any flutamide treated group. In conclusion, prenatal exposure to flutamide caused increased AR and KGF mRNA expression just after exposure, and an irreversible morphological change that is severest when the prostatic buds are developing in the ventral prostate. However the receptor binding capacity later in life was not affected.
日本毒性病理学会の論文
2003-12-30

Prenatal Exposure to Flutamide Induces Increased Keratinocyte Growth Factor mRNA, Irreversible Alteration of the Ductal Architecture, but No Change in Receptor Binding Capacity in the Rat Prostate Later in Life

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