Poster Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Induction of cytochrome P450 (CYP) 1A/1B mRNA expression by 7,12-dimethylbenz(a)anthracene (DMBA) is not dependent on AR mediated androgen actions in male or female mice (#213)

Francia Garces Suarez 1 , Yan Ru Gao 1 , David Handelsman 1 , Ulla Simanainen 1
  1. Anzac Research Institute, Concord , NSW, Australia

7,12-Dimethylbenz(a)anthracene (DMBA) is a model polycyclic aromatic hydrocarbon (PAH), compounds that are highly toxic, mutagenic and/or carcinogenic in the environment. DMBA is a widely used carcinogen in experimental breast cancer studies with most PAH effects mediated via the aryl hydrocarbon receptor (AHR). Ligand activated AHR induces the transcription of multiple target genes including cytochrome P450 (CYP) 1A/1B required for enzymatic activation of DMBA. Androgen action mediated via the androgen receptor (AR) is suggested to determine the sex dependent xenobiotic-inducible expression of CYP1 enzymes [1]. As we demonstrated AR dependent induction of DMBA-induced experimental mammary tumors in mice [2], we examined the AR-dependent regulation of Ahr and AHR nuclear translocator (Arnt) as well as DMBA-induced expression of Cyp1A and Cyp1B  mRNA in mouse liver and mammary gland by comparing gene expression in androgen insensitive, AR knockout (ARKO) and wild-type (WT) control mice. Mature (8-10 weeks of age) male and female WT and ARKO mice were treated with a single dose of DMBA (1 mg) or sesame oil vehicle (by gastric gavage) and tissues collected either 24 or 72 hours after treatment. In the liver, Cyp1A1 and Cyp1A2 mRNA expression was significantly induced by 24h after DMBA treatment in male and female mice independent of the genotype but gene expression returned to baseline by 72 hours after DMBA treatment. By contrast in female mammary tissue, Cyp1A1, but not Cyp1B1, expression was significantly induced at 72 hr after DMBA exposure. Expression of Ahr and Arnt genes were not affected by DMBA treatment, genotype or gender. These findings show that AR mediated androgen action does not significantly regulate murine Ahr or Arnt or PAH induced Cyp1 enzyme mRNA expression.

  1. 1. Kojima M, Sekimoto M, Degawa M: Androgen-mediated down-regulation of CYP1A subfamily genes in the pig liver. J Endocrinol 2010, 207(2):203-211.
  2. 2. Simanainen U, Gao YR, Walters KA, Watson G, Desai R, Jimenez M, Handelsman DJ: Androgen resistance in female mice increases susceptibility to DMBA-induced mammary tumors. Hormones & cancer 2012, 3(3):113-124.