Thomas Cadoudal, Véronique Lenoir, Graziella Penot, Indika SH Sathish, Yueqin Zhao, Xavier Coumoul, Claude Forest and Bernard Kerdelhue
Purpose: The promotion of mammary adenocarcinoma induced by Dimethyl benz (a) Anthracene (DMBA) is preceded by disruptions of the Hypothalamo-Pituitary-Gonadal and Hypothalamo-Pituitary-Adrenal axes and by a reduction of the secretion of Melatonin. We hypothesized that these disruptions might be induced by changes, in neuroendocrine structures of the brain, in the gene expression of receptors for Aryl Hydrocarbon (AHR) and 17β-Estradiol (ERS1 and ERS2).
Methods: Sprague Dawley female rats received one single administration of DMBA (75 mg/kg) at 52-55 days of age and were ovariectomized 5 days later. Then, one month later, RNAs from the Pineal Gland, the Hippocampus and the Hypothalamus were prepared and analyzed by real-time PCR for the presence of the transcripts encoding receptors for AHR and 17β-Estradiol (ERS1 and ERS2) together with those encoding Gonadotropin Releasing Hormone (GNRH1),Corticotropin Releasing Hormone (CRH) and Hydroxy-Indol-O-Methyl-Transferase (ASMT),the rate limiting enzyme for the synthesis of Melatonin.
Results: There was a long lasting and almost identical decrease in the expression of AHR, ERS1 and ERS2 in the Hypothalamus and the Pineal Gland. Also, there was an increase in the expression of ASMT and GNRH1 genes in the Pineal Gland, and of the GNRH1 gene in the Hypothalamus.However and, very interestingly, no effect was seen for the expression of any investigated gene in the Hippocampus, a structure of the brain implicated in cognition.
Conclusion: DMBA reduces the brain expression of AHR, ERS1 and ERS2, key transcriptional factors, but only in brain structures involved in the control of neuroendocrine systems.