title: The chemokine CCL2 protects against methylmercury neurotoxicity.
abstract: Industrial pollution due to heavy metals such as mercury is a major concern for the environment and public health. Mercury, in particular methylmercury (MeHg), primarily affects brain development and neuronal activity, resulting in neurotoxic effects. Because chemokines can modulate brain functions and are involved in neuroinflammatory and neurodegenerative diseases, we tested the possibility that the neurotoxic effect of MeHg may interfere with the chemokine CCL2. We have used an original protocol in young mice using a MeHg-contaminated fish-based diet for 3 months relevant to human MeHg contamination. We observed that MeHg induced in the mice cortex a decrease in CCL2 concentrations, neuronal cell death, and microglial activation. Knock-out (KO) CCL2 mice fed with a vegetal control food already presented a decrease in cortical neuronal cell density in comparison with wild-type animals under similar diet conditions, suggesting that the presence of CCL2 is required for normal neuronal survival. Moreover, KO CCL2 mice showed a pronounced neuronal cell death in response to MeHg. Using in vitro experiments on pure rat cortical neurons in culture, we observed by blockade of the CCL2/CCR2 neurotransmission an increased neuronal cell death in response to MeHg neurotoxicity. Furthermore, we showed that sod genes are upregulated in brain of wild-type mice fed with MeHg in contrast to KO CCL2 mice and that CCL2 can blunt in vitro the decrease in glutathione levels induced by MeHg. These original findings demonstrate that CCL2 may act as a neuroprotective alarm system in brain deficits due to MeHg intoxication.
authors: INSERM UMRS 968, Institut de la Vision, Université Pierre et Marie Curie Paris 6, 75012 Paris, France.
authors: David
authors: D
authors: Godefroy
authors: Romain-Daniel
authors: RD
authors: Gosselin
authors: Akira
authors: A
authors: Yasutake
authors: Masatake
authors: M
authors: Fujimura
authors: Christophe
authors: C
authors: Combadière
authors: Régine
authors: R
authors: Maury-Brachet
authors: Muriel
authors: M
authors: Laclau
authors: Randeep
authors: R
authors: Rakwal
authors: Stéphane
authors: S
authors: Melik-Parsadaniantz
authors: Jean-Paul
authors: JP
authors: Bourdineaud
authors: William
authors: W
authors: Rostène
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000493:pharmacokinetics / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D020262:Mercury Poisoning, Nervous System / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008767:Methylmercury Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004785:Environmental Pollutants; D008767:Methylmercury Compounds; D013482:Superoxide Dismutase; C004925:methylmercuric chloride