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《Chinese Journal of Preventive Medicine》 2004-04
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Study on the mechanism of male reproductive toxicity of metadoxine in mice and rats

ZHU Hui-juan *,KE Xue-qin,ZHU Xin-qiang,ZHENG Yi-fan,SHI Hong,XUE Zhen-yu. *Toxicology Department,School of Public Helth,Zhejiang University,Hangzhou 310031,China  
Objective To study the mechanism of male reproductive toxicity of metadoxine (MTDX) on mice and rats. Methods Mouse multiple endpoints assay and Hershberger assay were employed to evaluate the potential estrogenic and/or antiandrogenic effects of MTDX. In mouse multiple endpoints assay,MTDX (0,640,1 500 and 4 000 mg/kg,respectively) were administered once daily p.o. for 5 days in sexually matured and ovariectomied female NIH mice. Five endpoints evaluated as markers of estrogenicity included the ratio of uterine weight to body weight,incidence and extent of uterine fluid imbibition (hydrometra),vaginal epithelial cornification during estrous cycle (estrinization) and thickness of uterine epithelial cell and stroma cell. In Hershberger assay,MTDX (0,600 and 1 500 mg/kg,respectively) was administered once daily p.o. for 10 days to castrated male SD rats with or without testosterone propionate (TP,12.5 mg/kg,i.p. for 10 days) substitution. Relative weight of androgen dependent issues was measured. Results In mouse multiple endpoints assay,ratio of uterine weight to body weight was 1.33,1.38 and 1.31×10 -4 in MTDX 640,1 500 and 4 000 mg/kg groups, respectively,without significant difference from that in control group (1.22×10 -4 ). Thickness of uterine uterine epithelial cell (0.90 and 1.03 μm) and stroma cell (3.38 and 3.25 μm) in MTDX 1 500 and 4 000 mg/kg groups was not significantly different from the control group (0.85 μm and 2.77 μm,respectively). In Hershberger assay,relative weight of prostate plus seminal vesicle,levator ani muscle and bulbocavernous muscle was 1.13,0.17 and 0.42,respectively,in the 1 500 mg/kg group,significantly decreased as compared with those in the control group (1.46,0.24 and 0.70,respectively) ( P 0.01). Relative weight of prostate plus seminal vesicle (1.29) in the MTDX 600 mg/kg group reduced slightly,with statistical significance ( P 0.05),as compared with that in the control group(1.46). Conclusions In the present study,MTDX did not exhibit any estrogenic effect in mice in vivo . However,it had antiandrogenic activity in castrated male SD rats,indicating that its antiandrogenic effect nay be involved in it’s male reproductive toxicity.
【CateGory Index】: R114
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