Effect of the herbicide pendimethalin on rat uterine weight and gene expression and in silico receptor binding analysis.
The endocrine disrupting potential of the herbicide pendimethalin was investigated in vivo on the uterotrophic response and on the expression of estrogen-regulated genes examined by quantitative real-time RT PCR. Receptor binding characteristics of pendimethalin were analyzed by an in silico method. Pendimethalin (150, 225, 300 and 600 mg/kg/day) was administered by oral gavage to immature female rats for 3 days, with ethinylestradiol (0.001 mg/kg/day) as positive control. Pendimethalin caused a small but significant increase in absolute uterine weight at and above 300 mg/kg/day and in relative uterine weight at 600 mg/kg/day. Estrogen receptor (ER)-alpha mRNA levels were not affected, whereas ER-beta mRNA was up-regulated at the highest dose. Progesterone receptor mRNA level was not significantly changed, while insulin-like growth factor-I mRNA was reduced, significantly at 225 mg/kg/day to 65% of control. Androgen receptor (AR) mRNA showed a marked down-regulation at doses of 225 mg/kg/day and above. The expression pattern differed from that of ethinylestradiol. In silico analysis revealed potential binding of pendimethalin to ER-beta and AR, but virtually no binding to ER-alpha. These data demonstrate that pendimethalin exhibits estrogenic activity also in vivo. However, its uterotrophic effect, which is an ER-alpha-mediated response, is very small, and it appears that in vivo actions should rather be sought in ER-beta-regulated functions.
Undeğer
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Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Hacettepe University, Sihhiye, Ankara, Turkey. uundeger@hacettepe.edu.tr
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Lichtensteiger
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D000814:Aniline Compounds / Q000633:toxicity*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D019295:Computational Biology; D052244:Endocrine Disruptors / Q000633:toxicity*; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006540:Herbicides / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D011987:Receptors, Steroid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D000814:Aniline Compounds; D052244:Endocrine Disruptors; D047629:Estrogen Receptor beta; D006540:Herbicides; D012333:RNA, Messenger; D011987:Receptors, Steroid; C030856:pendimethalin