Neurological (motor and cognitive) alterations in rats perinatally exposed to three congeners of non 'dioxin-like' polychlorinated biphenyls congeners (pcbs 52, 138 or 180)molecular mechanisms involved

Resumen

Polychlorinated biphenyls (PCBs) are persistent organic pollutants present in human blood and milk. Exposure to PCBs during pregnancy and lactation leads to cognitive impairment and motor disorders in children. PCBs are classified in two groups depending on in their toxicological profile: 'dioxin-like' PCBs and non 'dioxin-like' PCBs. The effects produced by the first group are well known but less is known about the neurotoxic effect produced by the non 'dioxin-like'. The aim of this work was to assess whether exposure of rats to three different non dioxin-like PCBs congeners, PCB52, PCB138 or PCB180 during pregnancy and lactation affects the motor activity/coordination and the ability of the pups to learn a Y maze conditional discrimination task when there are 3-4 months old. We also studied the molecular mechanism involved in these alterations focusing in the role of group I mGluRs in striatum with the modulation of motor activity and also in the function of the glutamate-NO-cGMP pathway in cerebellum involved in the learning ability in the Y-maze. After finishing the motor and learning experiments, the modulation of group I mGluRs in striatum and the function of the glutamate-NO-cGMP pathway in cerebellum was analysed in the same rats by in vivo brain microdialysis. In collaboration with the 'Istituto di Ricercha Farmacologiche Mario Negri' in Milan (Italy) we also studied the changes in the proteomic profile in the cerebellum of the animals perinatally exposed to PCBs 52, 138 or 180. The results obtained show that (1) perinatal exposure to PCB138 but not to PCBs 52 or 180 slightly reduces the body weight gain in both male and female rats; (2) perinatal exposure to PCBs 138 or 180 but not to PCB 52 decreases spontaneous motor activity in male rats. In female rats, exposure to PCB 138 but not to PCBs 52 or 180 decreases motor activity; (3) perinatal exposure to PCBs 138 or 180 but not to PCB 52 alters the modulation of extracellular dopamine, glutamate and GABA by activation of group I mGluRs both in males and females This alteration may be involved in the reduced motor activity; (4) perinatal exposure to PCB 52 but not to PCBs 138 or 180 decreases motor coordination and also increases basal levels of extracellular GABA in cerebellum both in males and females; (5) perinatal exposure to PCBs 138 or 180 but not to PCB 52 impairs learning ability in the Y-maze and also impairs the function of the glutamate-NO-cGMP in cerebellum in vivo both in males and females; (6) perinatal exposure to PCBs 52, 138 or 180 alters the expression of proteins involved in the important cellular pathways such as the glycolisis- gluconeogenesis, the cytoskeleton remodelling and the GABA neurotransmission. The alterations in motor activity/coordination and in learning ability induced by developmental exposure to the NDL-PCBs reproduce some of the motor and cognitive disorders found in humans. 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.