Functional genomics may allow accurate categorization of the benzimidazole fungicide benomyl: lack of ability to act via steroid-receptor-mediated mechanisms.
Although benomyl and its metabolite carbendazim have been shown to adversely affect male reproduction, the mechanisms of action do not appear to involve the endocrine system. However, few studies have been conducted using currently proposed tests specifically focused on endocrine disruption. Here, potential estrogen- and androgen-mediated activity of benomyl was therefore investigated in vitro and in vivo. Benomyl and carbendazim proved negative for agonistic and antagonistic activity in reporter gene assays for the human estrogen receptor alpha and androgen receptor. In uterotrophic and Hershberger assays using Crj:CD(SD)IGS rats, benomyl (100, 300 or 1000 mg/kg/day, p.o., N = 6) did not exert agonistic effects. However, the highest dose decreased uterine weights in the uterotrophic assay, and decreased weights of some androgen-related tissues of castrated rats receiving a testosterone propionate (TP, 0.2 mg/kg) injection in the Hershberger assay; the effects were less severe than those with p,p'-DDE (100 mg/kg/day). When 4 mg/kg/day of TP was injected, decrease of organ weights due to benomyl was attenuated but still observed. Thus, its influence in some tissues was more potent than that of p,p'-DDE. Benomyl had no apparent effects on serum androgen levels. Microarray analysis of the gene expression profile in the ventral prostate of TP-injected castrated rats treated with benomyl indicated clear differences from the patterns observed with p,p'-DDE and flutamide. Taken together, these findings suggest the decreased organ weights observed in vivo to be caused by mechanisms that are not steroid-receptor-mediated, such as interfering with assembly of microtubules by benomyl. The study furthermore suggests that functional genomics may provide a reliable evidence for accurate categorization of test chemicals.
Yamada
Tomoya
T
Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd., Osaka, Japan. yamadat8@sc.sumitomo-chem.co.jp
Sumida
Kayo
K
Saito
Koichi
K
Ueda
Shinji
S
Yabushita
Setsuko
S
Sukata
Tokuo
T
Kawamura
Satoshi
S
Okuno
Yasuyoshi
Y
Seki
Takaki
T
D000284:Administration, Oral; D000818:Animals; D001542:Benomyl / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology; D001681:Biological Assay / Q000379:methods / Q000639:trends; D002219:Carbamates / Q000378:metabolism / Q000494:pharmacology; D003633:Dichlorodiphenyl Dichloroethylene / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000502:physiology; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D005659:Fungicides, Industrial / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods / Q000639:trends; D017930:Genes, Reporter / Q000187:drug effects / Q000235:genetics; D023281:Genomics / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects* / Q000502:physiology; D043343:Testosterone Propionate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects / Q000254:growth & development
D001562:Benzimidazoles; D002219:Carbamates; D047628:Estrogen Receptor alpha; D005659:Fungicides, Industrial; D011944:Receptors, Androgen; D004997:Ethinyl Estradiol; D003633:Dichlorodiphenyl Dichloroethylene; D005485:Flutamide; D008156:Luciferases; C006698:carbendazim; D001542:Benomyl; D043343:Testosterone Propionate