Neonatal C57BL/6J and parkin mice respond differently following developmental manganese exposure: Result of a high dose pilot study

• Published in: Neurotoxicology (Park Forest South) 2018-01, Vol.64, p.291-299
• Main Authors: Foster, Melanie L., Bartnikas, Thomas B., Maresca-Fichter, Hailey C., Mercadante, Courtney, Dash, Miriam, Miller, Chelsea, Dorman, David C.
• Format: Article
• Language: English
• Subjects: Adults; Animals; Animals, Newborn; Brain; Brain - drug effects; Brain - metabolism; Children; Cortex (frontal); Cortex (olfactory); Cortex gene; Exposure; Female; Femur; Gene expression; Health risks; Liver; Liver - drug effects; Liver - metabolism; Male; Manganese; Manganese - toxicity; Manganese compounds; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor activity; Motor Activity - drug effects; Mutation; Neonates; Neostriatum; Neurodegeneration; Neurotoxicity; Newborn babies; Olfactory bulb; Parkin protein; Parkinson's disease; Pharmacokinetics; Pilot Projects; Tissue Distribution; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2017.10.002

•Parkin and C57BL/6J mice have similar brain manganese (Mn) levels following neonatal Mn exposure.•Altered motor activity and hepatic gene expression was seen in C57BL/6J mice following Mn exposure.•The Parkin gene defect did not increase the susceptibility of neonatal mice to Mn toxicity. It has been suggested that childhood exposure to neurotoxicants may increase the risk of Parkinson’s disease (PD) or other neurodegenerative disease in adults. Some recessive forms of PD have been linked to loss-of-function mutations in the Park2 gene that encodes for parkin. The purpose of this pilot study was to evaluate whether responses to neonatal manganese (Mn) exposure differ in mice with a Park2 gene defect (parkin mice) when compared with a wildtype strain (C57BL/6J). Neonatal parkin and C57BL/6J littermates were randomly assigned to 0, 11, or 25mg Mn/kg-day dose groups with oral exposures occurring from postnatal day (PND) 1 through PND 28. Motor activity was measured on PND 19–22 and 29–32. Tissue Mn concentrations were measured in liver, femur, olfactory bulb, frontal cortex, and striatum on PND 29. Hepatic and frontal cortex gene expression of Slc11a2, Slc40a1, Slc30a10, Hamp (liver only), and Park2 were also measured on PND 29. Some strain differences were seen. As expected, decreased hepatic and frontal cortex Park2 expression was seen in the parkin mice when compared with C57BL/6J mice. Untreated parkin mice also had higher liver and femur Mn concentrations when compared with the C57BL/6J mice. Exposure to≥11mg Mn/kg-day was associated with increased brain Mn concentrations in all mice, no strain difference was observed. Manganese exposure in C57Bl6, but not parkin mice, was associated with a negative correlation between striatal Mn concentration and motor activity. Manganese exposure was not associated with changes in frontal cortex gene expression. Decreased hepatic Slc30a10, Slc40a1, and Hamp expression were seen in PND 29 C57BL/6J mice given 25mg Mn/kg-day. In contrast, Mn exposure was only associated with decreased Hamp expression in the parkin mice. Our results suggest that the Parkin gene defect did not increase the susceptibility of neonatal mice to adverse health effects associated with high-dose Mn exposure.