title: The systemic and gonadal toxicity of 3-methylcholanthrene is prevented by daily administration of α-naphthoflavone.
abstract: In the present study, we investigated the effect of 3-methylcholanthrene (3MC) on sexual maturity and the ability of α-naphthoflavone (αNF) to prevent this action. To this end, immature rats were daily injected intraperitoneally with 3MC (0.1 or 1mg/kg) and/or αNF (80mg/kg). Body weight, vaginal opening and estrous cycle were recorded and ovaries were obtained on the day of estrus. Ovarian weight, ovulation rate (measured by the number of oocytes within oviducts), and follicular development (determined by histology) were studied. No differences were found in body weight, ovarian weight, day of vaginal opening, or the establishment of the estrous cycle among the different groups of rats. However, animals treated with 3MC, at both doses, exhibited a lower number of primordial, primary, preantral and antral follicles than controls. Also, 3MC inhibited the ovulation rate and induced an overexpression of both the Cyp1a1 and Cyp1b1 genes, measured by chromatin immunoprecipitation assay. The daily treatment with αNF alone increased the number of follicles in most of the stages analyzed when compared with controls. Moreover, the αNF treatment prevented completely not only the 3MC-induced decrease in all types of follicles but also the 3MC-induced overexpression of Cyp enzymes and the genetic damage in bone marrow cells and oocytes. These results suggest that (i) daily exposure to 3MC during the pubertal period destroys the follicle reserve and alters the ovulation rate; (ii) the 3MC action seems to be mediated by an aryl hydrocarbon receptor-dependent mechanism; (iii) daily administration of αNF has a clear stimulatory action on the ovarian function; and (iv) αNF may prevent both the systemic and gonadal 3MC-induced toxicity.
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Eric Alejandro
authors.initials: EA
authors.lastname: Rhon-Calderón
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Rocío Alejandra
authors.initials: RA
authors.lastname: Galarza
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lomniczi
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: alifaletti@gmail.com.
authors.forename: Alicia Graciela
authors.initials: AG
authors.lastname: Faletti
mesh_terms: D000818:Animals; D001571:Benzoflavones / Q000008:administration & dosage* / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008748:Methylcholanthrene / Q000633:toxicity*; D009865:Oocytes / Q000187:drug effects / Q000473:pathology; D006080:Ovarian Follicle / Q000187:drug effects; D010060:Ovulation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism
chemical_list: D001571:Benzoflavones; D018336:Receptors, Aryl Hydrocarbon; D008748:Methylcholanthrene; C011512:alpha-naphthoflavone; C585499:Cyp1b1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1
keywords: 3-Methylcholanthrene; Follicular growth; Ovulation; α-Naphthoflavone