cyclic-gmp and 2-5-2--5--tetrachlorobiphenyl

Exposure to polychlorinated biphenyls (PCBs) during pregnancy and lactation leads to cognitive impairment and motor disorders in children by mechanisms which remain unknown. It also remains unclear whether different non-dioxin-like PCBs have similar or different mechanisms of neurotoxicity. The main aims of this work were: (1) to assess whether developmental exposure to non-dioxin-like-PCBs 52, 138 or 180 affect cognitive function or motor coordination in 3-4 months-old rats; (2) to shed light on the underlying mechanisms. Female rats were treated with PCBs (1 mg/kg day) in food from gestational-day 7 to postnatal-day 21. The ability to learn a Y maze conditional discrimination task was reduced in rats exposed to PCBs 138 or 180, but not in rats exposed to PCB52. The function of the glutamate-nitric oxide-cGMP pathway (NMDA-induced increase in extracellular cGMP) in cerebellum in vivo was reduced by 33-59% in rats exposed to PCBs 138 or 180, but not by PCB52. The amount of NR1 subunit of NMDA receptors was reduced by 41-49% in rats exposed to PCBs 138 or 180, but not by PCB 52. PCB52 but not 138 or 180 increases extracellular GABA in cerebellum and impairs motor coordination. The effects were similar in males and females. Developmental exposure to different non-dioxin-like PCBs induces different behavioural alterations by different mechanisms. PCB52 impairs motor coordination but not learning while PCB138 or 180 impair learning but not motor coordination. These data are consistent with the following possible mechanisms: (1) developmental exposure to PCBs 138 or 180 reduces the amount of NMDA receptors in cerebellum, which would contribute to reduced function of the glutamate-NO-cGMP pathway, which, in turn, would be a main contributor to the impairment of the ability to learn the Y maze task. (2) Developmental exposure to PCB52 increases extracellular GABA in cerebellum, which would contribute to motor coordination impairment.

Topics: Animals; Cerebellum; Cyclic GMP; Discrimination, Psychological; Environmental Pollutants; Extracellular Space; Female; gamma-Aminobutyric Acid; Glutamic Acid; Learning; Male; Maternal Exposure; Maze Learning; N-Methylaspartate; Polychlorinated Biphenyls; Pregnancy; Prenatal Exposure Delayed Effects; Psychomotor Performance; Rats; Receptors, N-Methyl-D-Aspartate; Sex Factors

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that accumulate in the food chain and are present in human blood and milk. Children born to mothers exposed to PCBs show cognitive deficits, which are reproduced in rats perinatally exposed to PCBs. It has been proposed that PCB-induced cognitive impairment is due to impairment of the glutamate-nitric oxide (NO)-cGMP pathway. The aim of the present work was to assess whether chronic exposure to the nondioxin-like PCB52, PCB138, or PCB180 alters the function of this pathway in primary cultures of rat cerebellar neurons and to assess whether different PCBs have similar or different mechanisms of action. PCB180 and PCB138 impair the function of the glutamate-NO-cGMP pathway at nanomolar concentrations, and PCB52 impairs the function of the glutamate-NO-cGMP pathway at micromolar concentrations. The mechanisms by which different PCBs impair the function of the glutamate-NO-cGMP pathway are different. Each PCB affects the pathway at more than one step but with different potency and, for some steps, in opposite ways. Exposure to the PCBs alters the basal concentrations of intracellular calcium, NO, and cGMP. The three PCBs increase NO; however, PCB52 and PCB138 increase basal cGMP, while PCB180 decreases it. PCB52 and PCB138 decrease the activation of soluble guanylate cyclase by NO, and PCB180 increases it. Long-term exposure to PCB52, PCB180, or PCB138 reduces the activation of NO synthase and the whole glutamate-NO-cGMP pathway in response to activation of N-methyl-d-aspartate receptors. The EC(50) was 300 nM for PCB52 and 2 nM for PCB138 or PCB180. These results show that chronic exposure to nondioxin like PCBs impairs the function of the glutamate-NO-cGMP pathway in cerebellar neurons by different mechanisms and with different potencies. Impaired function of this pathway would contribute to the cognitive alterations induced by perinatal exposure to PCBs in humans.

Topics: Animals; Cells, Cultured; Cerebellum; Cyclic GMP; Environmental Exposure; Environmental Pollutants; Glutamic Acid; Guanylate Cyclase; Neurons; Nitric Oxide; Nitric Oxide Synthase; Polychlorinated Biphenyls; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, N-Methyl-D-Aspartate; Soluble Guanylyl Cyclase