[Study on the mechanism of male reproductive toxicity of metadoxine in mice and rats].
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, 1500 and 4000 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 1500 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 x 10(-4) in MTDX 640, 1500 and 4000 mg/kg groups, respectively, without significant difference from that in control group (1.22 x 10(-4)). Thickness of uterine uterine epithelial cell (0.90 and 1.03 microm) and stroma cell (3.38 and 3.25 microm) in MTDX 1500 and 4000 mg/kg groups was not significantly different from the control group (0.85 microm and 2.77 microm, 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 1500 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 may be involved in it's male reproductive toxicity.
Zhu
Hui-Juan
HJ
Toxicology Department, School of Public Helth, Zhejiang University, Hangzhou 310031, China.
Ke
Xue-Qin
XQ
Zhu
Xin-Qiang
XQ
Zheng
Yi-Fan
YF
Shi
Hong
H
Xue
Zhen-Yu
ZY
D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D004338:Drug Combinations; D023381:Endpoint Determination; D005260:Female; D005837:Genitalia, Male / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D009919:Orchiectomy; D010052:Ovariectomy; D011736:Pyridoxine / Q000633:toxicity*; D011761:Pyrrolidonecarboxylic Acid / Q000633:toxicity*; D051381:Rats
D000726:Androgen Antagonists; D004338:Drug Combinations; C037845:metadoxine; D011736:Pyridoxine; D011761:Pyrrolidonecarboxylic Acid