title: Enhanced susceptibility of ovaries from obese mice to 7,12-dimethylbenz[a]anthracene-induced DNA damage.
abstract: 7,12-Dimethylbenz[a]anthracene (DMBA) depletes ovarian follicles and induces DNA damage in extra-ovarian tissues, thus, we investigated ovarian DMBA-induced DNA damage. Additionally, since obesity is associated with increased offspring birth defect incidence, we hypothesized that a DMBA-induced DNA damage response (DDR) is compromised in ovaries from obese females. Wild type (lean) non agouti (a/a) and KK.Cg-Ay/J heterozygote (obese) mice were dosed with sesame oil or DMBA (1mg/kg; intraperitoneal injection) at 18weeks of age, for 14days. Total ovarian RNA and protein were isolated and abundance of Ataxia telangiectasia mutated (Atm), X-ray repair complementing defective repair in Chinese hamster cells 6 (Xrcc6), breast cancer type 1 (Brca1), Rad 51 homolog (Rad51), poly [ADP-ribose] polymerase 1 (Parp1) and protein kinase, DNA-activated, catalytic polypeptide (Prkdc) were quantified by RT-PCR or Western blot. Phosphorylated histone H2AX (γH2AX) level was determined by Western blotting. Obesity decreased (P<0.05) basal protein abundance of PRKDC and BRCA1 proteins but increased (P<0.05) γH2AX and PARP1 proteins. Ovarian ATM, XRCC6, PRKDC, RAD51 and PARP1 proteins were increased (P<0.05) by DMBA exposure in lean mice. A blunted DMBA-induced increase (P<0.05) in XRCC6, PRKDC, RAD51 and BRCA1 was observed in ovaries from obese mice, relative to lean counterparts. Taken together, DMBA exposure induced γH2AX as well as the ovarian DDR, supporting that DMBA causes ovarian DNA damage. Additionally, ovarian DDR was partially attenuated in obese females raising concern that obesity may be an additive factor during chemical-induced ovotoxicity.
authors.affiliation: Department of Animal Science, Iowa State University, Ames, IA 50011, USA. Electronic address: shanthig@iastate.edu.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Animal Science, Iowa State University, Ames, IA 50011, USA. Electronic address: nteeba@iastate.edu.
authors.forename: Jackson
authors.initials: J
authors.lastname: Nteeba
authors.affiliation: Department of Animal Science, Iowa State University, Ames, IA 50011, USA. Electronic address: akeating@iastate.edu.
authors.forename: Aileen F
authors.initials: AF
authors.lastname: Keating
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D005819:Genetic Markers; D006657:Histones / Q000378:metabolism; D000072200:Ku Autoantigen; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
chemical_list: D034961:Antigens, Nuclear; D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; C475961:gamma-H2AX protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen
keywords: DMBA; DNA double strand breaks; DNA repair; Obesity; Ovary; Ovotoxicity