Journal
TOXICOLOGY REPORTS
Volume 2, Issue -, Pages 1046-1056Publisher
ELSEVIER
DOI: 10.1016/j.toxrep.2015.07.015
Keywords
Iron; Manganese; Rat; Preweaning developmenta
Categories
Funding
- NIH [R01ES15689]
- NRSA [ES007051, P30ES006096]
- NCATS NIH HHS [UL1 TR001425] Funding Source: Medline
- NIEHS NIH HHS [R01 ES015689, T32 ES007051] Funding Source: Medline
- NIEHS NIH HHS [P30 ES006096, R01 ES015689, T32 ES007051] Funding Source: Medline
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Manganese overexposure (MnOE) can be neurotoxic. In humans this can occur through occupational exposure, air or water contamination, well water, soy milk, and some baby formulas. In children MnOE has been associated with cognitive and behavioral deficits. The effects of MnOE may be modified by factors such as iron status. We hypothesized that developmental MnOE would be exacerbated by iron deficiency. A diet with a 90% decrease in iron (FeD) was given to gravid female rats starting on embryonic day 15 and continued through postnatal day (P) 28. Mn (100 mg/kg) or vehicle (VEH) was administered by gavage every other day from P4-28. Metal transporters and receptors (divalent metal transporter-1 (DMT1), transferrin (Tf), transferrin receptor (TfR), and Zrt-Irt-like protein 8 (ZIP8)) were quantified in brain at P28. These markers were increased but the changes were specific: MnOE increased TfR and decreased Tf in hippocampus, whereas FeD increased TfR in neostriatum and increased TfR and DMT1 in the hippocampus, and the combination increased TfR in neostriatum (ZIP8 was unaffected). Identically treated animals were tested behaviorally at P29 or P60. The combination of FeD + MnOE increased head dips in an elevated zero-maze, reversed deficits in sucrose preference induced by MnOE alone, and increased spontaneous locomotion in an open-field. Rats were also evaluated for changes in locomotor activity after challenge with (+/-)-fenfluramine (FEN, a 5-HT agonist: 5 mg/kg), MK-801 (MK801, an NMDA antagonist: 0.2 mg/kg), or (+)-amphetamine (AMPH, a dopamine agonist: 1 mg/kg). Compared with VEH animals, MnOE animals were more hyperactive after amphetamine or MK-801, and were less inhibited after fenfluramine, regardless of FeD exposure. The results indicate persistent effects of developmental MnOE on brain and behavior but few interactions with dietary iron deficiency. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
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