Sex as a major determinant of gene expression in tissues of mice exposed to arsenate.

Inorganic arsenic, frequently found as contaminant of ground water used for drinking purposes in many areas of the world, is a well-known potent human toxicant and carcinogen. Chronic exposure to inorganic arsenic has been associated with cancer of skin, lung, bladder and kidney and, probably, liver. The mechanism of arsenic action in vivo is poorly understood, in particular in relation to dose, type of tissue and gender. To elucidate tissue- and gender dependent biological responses in the genome of mice, we have used cDNA macroarrays for investigation on the expression of 1185 cancer-related genes in mice after exposure to arsenate in drinking water. Continuous exposures of mice to arsenate in drinking water modulate the gene expression in tissues. Interestingly, there were remarkable sex differences: male and female mice show completely different changes in the expression of cancer-related genes. The main gene functional families modulated, were covering a wide range of biochemical and physiological regulations, like cell cycle modulation, cell adhesion, apoptosis, xenobiotic metabolism, DNA repair, protein turnover and proto-oncogens. This result demonstrates important gene-environmental interactions: the molecular mechanisms triggered by arsenic levels frequently experienced following exposure via drinking water, are totally different in males and females. The results obtained using cancer-related genes will be compared with the profiles of over 30.000 genes using the Applied Biosystems expression Array System, to clarify the sex-specific gene pathways.