title: Functional genomics may allow accurate categorization of the benzimidazole fungicide benomyl: lack of ability to act via steroid-receptor-mediated mechanisms.
abstract: 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.
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd., Osaka, Japan. yamadat8@sc.sumitomo-chem.co.jp
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamada
authors.forename: Kayo
authors.initials: K
authors.lastname: Sumida
authors.forename: Koichi
authors.initials: K
authors.lastname: Saito
authors.forename: Shinji
authors.initials: S
authors.lastname: Ueda
authors.forename: Setsuko
authors.initials: S
authors.lastname: Yabushita
authors.forename: Tokuo
authors.initials: T
authors.lastname: Sukata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawamura
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Okuno
authors.forename: Takaki
authors.initials: T
authors.lastname: Seki
mesh_terms: 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
chemical_list: 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