Sexual dimorphism of hepatic genes expressed in hexachlorobenzène treated rats.

Alt, Benjamin (2003). Sexual dimorphism of hepatic genes expressed in hexachlorobenzène treated rats. Mémoire. Québec, Université du Québec, Institut National de la Recherche Scientifique, Maîtrise en sciences expérimentales de la santé, 124 p.

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Résumé

Hexachlorobenzene (HCB) is an epigenetic carcinogen that is persistent in the environment and has a tendency to bio-accumulate. HCB is stored in fatty tissues of animais and humans. When rats are exposed to HCB, females are more susceptible to develop tumors as compared to males. The genes responsible for such an expression are poorly understood. The objective of this study was to determine the gender-specific hepatic gene expression profiles observed in rats exposed to HCB. Four experimental groups were used; control males; control females; HCB-treated males and HCB-treated females. Treated rats were exposed to HCB (100 mg/kg) for five consecutive days and sampled on day 50 of the experiment. The in vivo exposure model used in the present study in which rats are sampled at day 50 represents a "steady state" situation following from HCB exposure. Total RNA was isolated from the liver and reverse transcribed and used to screen an Atlas™ 1.2 II Rat Array containing 1176 genes. Data were analyzed using four individual rats per experimental group. Genes expressed in at least 3 out of 4 trials were selected for analysis. In addition, the genes must have had signal intensities at least 2X background level. Our data indicates a sexual dimorphism in the expression of hepatic genes due to HCB-treatment. The female control group displayed comparable gene expression as the male control group (185 versus 184 genes). Seven genes were exclusively found in the male control group; ERp29, synaptogyrin 1, synaptojanin, DPPIII, kinesin-related protein, atrophin 1 and glycoprotein 55. Two genes were exclusively expressed in females; Mammalian achaete scute homolog 2 (MASH-2) and carboxypeptidase z. In HCB-treated males a total of 189 genes were detected by the eDNA microarray. Four of those genes had significant differentiai expressions; EGR2, dihydropyrimidinase and a liver-specific transport protein were down-regulated while epoxide hydrolase, an enzyme involved in the biotransformation of xenobiotics and epoxides was up-regulated. No genes were exclusively expressed in HCB-treated females. However, HCB caused an 18% decrease (31 genes) in the total number of genes detected by the microarray in livers of HCB-treated females compared to control females. Twenty-nine percent of the 31 genes decreased in HCB-treated females have already been reported to be down-regulated in liver cancer. Furthermore we noticed a sexual dimorphism at the genetic level since in HCB-treated females surprisingly only 151 were expressed among which five genes were differentially expressed in HCB-treated females only; phosphatidylethanolamine N-methyltransferase, phosphatidylethanolamine binding­ protein, ribosomal protein L18 and testis-specific farnesyl pyrophosphate were up­ regulated while protectin/CD59 was repressed. Thirty-six genes were altered by HCB treatment and may be implicated in the epigenetic mechanism of HCB-induced hepatocarcinogenesis. Of those genes 31 were found to be putative tumor suppressor genes whose mRNA levels were undetectable in HCB-treated females and 5 that showed sexual dimorphism in terms of genetic expression. The functional genomic approach used in this study bas enabled us to target and identify trends in the expressions of clusters/families of genes that have been linked to HCB-induced hepatocarcinogenesis in HCB-treated females only. The results of this study expose additional insights into the mechanisms underlying HCB carcinogenesis. We propose a primary mechanism by which HCB alters the DNA methylation machinery of the cell, a known factor implicated in epigenetic carcinogens and reported to contribute to the early steps of carcinogenesis.

Type de document:	Thèse Mémoire
Directeur de mémoire/thèse:	Cyr, Daniel G.
Co-directeurs de mémoire/thèse:	Charbonneau, Michel
Mots-clés libres:	hcb ; hexachlorobenzene ; porphyrie
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	12 févr. 2014 19:42
Dernière modification:	08 déc. 2015 14:59
URI:	https://espace.inrs.ca/id/eprint/2052

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