Developmental exposure to polychlorinated biphenyls PCB153 or PCB126 impairs learning ability in young but not in adult rats Blanca Piedrafita, Slaven Erceg, Omar Cauli, Pilar Monfort and Vicente Felipo Laboratory of Neurobiology, Centro de Investigacion Prı ´ncipe Felipe, Avda Autopista del Saler, 16, 46013 Valencia, Spain Keywords: cognitive function, cyclic GMP, nitric oxide, NMDA receptors, PCBs Abstract Polychlorinated biphenyls (PCBs) are persistent organic pollutants present in the food chain and in human blood and milk. Exposure to PCBs during pregnancy and lactation leads to cognitive impairment in children. The underlying mechanisms remain unclear. Some PCBs are endocrine disrupters. The aim of this work was to assess whether exposure of rats to PCB126 (dioxin-like) or PCB153 (non-dioxin-like) during pregnancy and lactation affects the ability of the pups to learn a Y maze conditional discrimination task and ⁄ or the function of the glutamate–nitric oxide (NO)–cGMP pathway in brain in vivo when the rats are young (3 months) or adult (7–8 months). After finishing the learning experiments, the function of the pathway was analysed in the same rats by in vivo brain microdialysis. The results obtained show that perinatal exposure to PCB153 or PCB126: (1) impairs learning ability in young but not in adult rats, (2) impairs the glutamate–NO–cGMP pathway function in cerebellum in vivo in young but not in adult rats and (3) affect these parameters in males and females similarly. PCB126 is around 10 000-fold more potent than PCB153. In control rats the function of the glutamate–NO–cGMP pathway and learning ability are lower in adult than in young rats. These age-related differences are not present in rats exposed to PCBs. The impairment of the glutamate–NO–cGMP pathway function induced at young age by developmental exposure to the PCBs could be one of the mechanisms contributing to the cognitive impairment found in children whose mothers ingested PCB-contaminated food during pregnancy and lactation. Introduction Polychlorinated biphenyls (PCBs) are a family of 209 industrial chemicals which are persistent organic pollutants and are toxic and endocrine disrupters (Safe, 1994). They accumulate in the food chain and humans are exposed to PCBs through diet. PCBs are present in human blood and milk (Fangstrom et al., 2005; Inoue et al., 2006). Children born from mothers exposed to PCBs show memory deficits and cognitive dysfunctions as well as sensory and motor disorders (Jacobson & Jacobson, 1996; Schantz et al., 1996; Faroon et al., 2001; Landrigan, 2001), indicating that developmental exposure to PCBs is neurotoxic and affects cerebral function. Perinatal exposure of rodents or monkeys to PCBs also results in altered cerebral function and in neurological alterations (Lilienthal et al., 1990; Schantz et al., 1995, 1997; Rice & Hayward, 1999; Roegge et al., 2000). PCBs have a common biphenyl structure but the different patterns and number of chlorine substitutions provides very different chemical properties between congeners, which also determines their biological effects. PCBs have been classified according to their structure in coplanar and non-coplanar types, depending on the position of the benzene rings, and also into ‘dioxin-like’ (among the coplanar) and ‘non-dioxin-like’ based on their toxicological profile. For instance, the dioxin-like PCBs, such as PCB126, bind to the Ah-receptor, producing endocrine disruption in experimental animals, as with dioxins, and are considered to be far more toxic than non-dioxin-like PCBs (Giesy & Kannan, 1998; Aoki, 2001; Faroon et al., 2003). However, non-dioxin- like PCBs (such as PCB153) account for a majority of the mass of the PCBs found in environmental and biological samples and some congeners have been described as carcinogens or interfering in neurotransmitter release (Faroon et al., 2001). Both types of PCBs have been associated with neurodevelopmental deficits (Faroon et al., 2001) but it is not clear whether the mechanisms of neurotoxicity of dioxin-like and non-dioxin-like congeners are similar or different and whether the effects of PCBs could be different in males and females. Eriksson et al. (2006) showed that motor defects worsen with age in mice neonatally exposed to PCB52 and polybrominated diphenyl ether 99. It is unclear whether the cognitive effects of developmental exposure to PCBs are similarly expressed at different ages or are preferentially expressed during youth or maturity. The molecular mechanisms by which developmental exposure to PCBs affect cerebral and cognitive functions remain unclear. NMDA receptors play a crucial role in some types of learning (Riedel et al., 2003). Activation of NMDA receptors leads to increased calcium in the postsynaptic neuron, leading to activation of neuronal nitric oxide synthase and increased nitric oxide (NO), which, in turn, activates soluble guanylate cyclase, increasing cGMP. Part of this cGMP is released to the extracellular fluid. Activation of this glutamate– NO–cGMP pathway modulates some forms of learning (Danysz et al., 1995; Chen et al., 1997; Meyer et al., 1998). The function of this glutamate–NO–cGMP pathway is impaired in brain in vivo in some pathological situations such as rats with chronic hyperammonemia (Hermenegildo et al., 1998) or liver failure (Monfort et al., 2001). These rats also show reduced ability to learn a conditional Correspondence: Dr. V. Felipo, as above. E-mail: vfelipo@cipf.es Received 16 July 2007, revised 7 November 2007, accepted 12 November 2007 European Journal of Neuroscience, pp. 1–6, 2007 doi:10.1111/j.1460-9568.2007.05988.x ª The Authors (2007). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd