Gender is one of the most important factors in mammalian development and response to exogenous agents. Although there is increasing evidence that health effects of toxic xenobiotics differ in prevalence or are manifested differently in male and female, the molecular mechanisms related to these events remain unclear. In order to investigate the possible influence of gender, male and female Wistar rats from the same litter were exposed to zinc chloride (5 mg ⁄ kg, i.p.) or malathion (250 mg ⁄ kg, i.p.) 24 hr prior to the analyses of biochemical parameters related to the cholinergic and glutathione-antioxidant systems in cerebral cortex and hippocampus. After treatments, acetylcholinesterase (AChE) activity was reduced in the hippocampus and cerebral cortex of male and female rats treated with malathion, but the effect was more pronounced in the male group. Glutathione reductase (GR) and c-glutamyl-transpeptidase activities were reduced in the hippocampus of males and females and a gender-specific effect of malathion was seen for glutathione S-transferase (GST), which was decreased only in male hippocampus and cortex, and for male cortical GR. Zinc chloride treatment decreased AChE activity in male and female cerebral cortex, with no obvious effect in the hippocampus. Male-specific antioxidant-related enzyme activity reductions were seen after zinc treatment for cortical GR, GST, glutathione peroxidase and glucose-6-phosphate dehydrogenase; and hippocampal GR. These results clearly demonstrate a greater detrimental effect on antioxidant-related enzyme activities in male hippocampus and cerebral cortex when rats were acutely exposed to malathion and zinc, demonstrating that the research on gender-related differences in health effects caused by xenobiotic and ⁄ or essential elements requires further attention.Gender-based differences in the metabolism constitute a major topic in biology, and sex-dependent toxicity permeates the literature for a series of factors. Some examples of research areas where gender differences are important determinants of toxicity are: metal toxicity [1], pharmacokinetics [2], hormone metabolism [3], xenobiotics metabolism [4] and traumatic injury vulnerability [5]. The relevance of studying gender-dependent toxicity has been stressed before: 'Gender may be the most important factor in mammalian development and response to exogenous agents' [6].Incidental or intentional organophosphate intoxication is a relevant health problem in developing countries [7]. Despite the limitation of population analysis, neurobehavioural impairment might be the consequence of an acute poisoning, and possibly the consequence of relatively high and prolonged exposure [8]. Organophosphate has been considered as an important risk factor for depression and correlated to suicide attempts [9] and has been used as a model of depressive-like behaviour in animals [10]. Malathion, a pesticide widely used to fight fleas, lice, mosquitoes and flies, is thought to be one of the main agents leading to human organop...