Environmental Toxicology and Pharmacology 27 (2009) 293–297 Contents lists available at ScienceDirect Environmental Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/etap 17-estradiol decreases methylmercury-induced neurotoxicity in male mice Keller Samara Malagutti a , Aline Preve da Silva a , Hugo Campos Braga a , Péricles Arruda Mitozo b , Adair Roberto Soares dos Santos b , Alcir Luiz Dafre b , Andreza Fabro de Bem a , Marcelo Farina a,∗ a Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil b Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil article info Article history: Received 3 September 2008 Received in revised form 9 November 2008 Accepted 12 November 2008 Available online 21 November 2008 Keywords: Methylmercury Gender 17-estradiol Oxidative stress abstract There is increasing evidence that health effects of toxic metals, including methylmercury (MeHg), differ in prevalence or are manifested differently in men and women. The present study was aimed at inves- tigating the potential differential susceptibility of male and female Swiss mice against MeHg-induced neurotoxicity, which was evaluated by biochemical (cerebellar oxidative stress-related parameters) and behavioral (locomotor activity and motor performance) variables. We also aimed to evaluate the potential protective effects of 17-estradiol against such toxicity in MeHg-exposed male animals. MeHg exposure (40mg/L, diluted in tap water, during 2 weeks) decreased locomotor activity and motor performance in both male and female animals, but such phenomena were higher in males. 17-estradiol co-treatment (10 g/animal, in alternate days) prevented MeHg-induced locomotor deficits in males. MeHg exposure caused a significant increase (60%) in cerebellar lipid peroxidation in male mice, but did not in females. In close agreement, MeHg exposure decreased (43%) cerebellar glutathione peroxidase activity in males, but did not in females. These events were prevented by 17-estradiol administration. Cerebellar GR activity was increased (25%) in MeHg-exposed males and such event was partially prevented by 17-estradiol administration. These results indicate that the low susceptibility of female mice to the neurotoxicity elicited by MeHg is linked to neuroprotective effects of sex steroids, which appear to modulate the activities of glutathione-related enzymes. Our experimental observation corroborates previous epidemi- ological studies showing the greater developmental effects in male than in female humans exposed to MeHg. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Methylmercury (MeHg) is a highly neurotoxic compound that induces neurological and developmental deficits in animals and humans (Clarkson et al., 2003; Johansson et al., 2007). A number of synchronous mechanisms are likely associated with MeHg-induced neurotoxicity, including impairment of intracellular calcium home- ostasis (Sirois and Atchison, 2000; Atchison, 2005), alteration of glutamate homeostasis (Aschner et al., 2000; Farina et al., 2003a; Soares et al., 2003) and oxidative stress (Manfroi et al., 2004; Yin et al., 2007; Franco et al., 2007). MeHg-induced oxidative stress is related to its direct chemical interaction with nonenzymatic antiox- idants, such as glutathione (Stringari et al., 2006), as well as changes in the activities of antioxidant enzymes (Farina et al., 2003b, 2005; Franco et al., 2006; Carvalho et al., 2007). Notably, MeHg-induced oxidative stress and MeHg-induced glutamate dyshomeostasis are ∗ Corresponding author. Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-900, Campus Trindade, Florianópolis, SC, Brazil. Tel.: +55 48 3721 9589; fax: +55 48 3721 9672. E-mail address: farina@ccb.ufsc.br (M. Farina). connected phenomena affecting each other (Aschner et al., 2007). In fact, MeHg-induced inhibition of astrocyte glutamate transporters leads to increased glutamate concentrations in the extracellular fluid, causing hyperactivation of N-methyl d-aspartate (NMDA)- type glutamate receptors and leading to an increase in Na + and Ca 2+ influx (Choi, 1992). Increased intracellular Ca 2+ levels are associated with the generation of reactive oxygen species (Lafon-Cazal et al., 1993). On the other hand, MeHg-induced reactive oxygen species (mainly H 2 O 2 ) production appears to directly inhibit astrocyte glu- tamate transporters, leading to increased glutamate concentrations in the extracellular fluid (Allen et al., 2001). Gender-dependent MeHg metabolism has been reported in humans (Miettinen, 1973) and in experimental animals (Hirayama et al., 1987). In this regard, gender differences in the excretion, distribution, and retention of organic and inorganic mercury in MeHg treated rats show faster whole body clearance of the metal in females than in males (Thomas et al., 1986, 1987). Epidemiolog- ical studies with human infants and children (McKeown-Eyssen et al., 1983; Grandjean et al., 1998), as well as experimental animal studies (Rossi et al., 1997; Gimenez-Llort et al., 2001; Björklund et al., 2007), have reported greater neurotoxic effects in males than in females exposed to MeHg. Although these evidences point 1382-6689/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.etap.2008.11.005