Manganese-induced NF-kappaB activation and nitrosative stress is decreased by estrogen in juvenile mice

Document Type

Article

Abstract

Manganese toxicity can cause a neurodegenerative disorder affecting cortical and basal ganglia structures with a neurological presentation resembling features of Parkinson's disease. Children are more sensitive to Mn-induced neurological dysfunction than adults, and recent studies from our laboratory revealed a marked sensitivity of male juvenile mice to neuroinflammatory injury from Mn, relative to females. To determine the role of estrogen (E2) in mediating sex-dependent vulnerability to Mn-induced neurotoxicity, we exposed transgenic mice expressing an NF-κB-driven enhanced green fluorescent protein (EGFP) reporter construct (NF-κB-EGFP mice) to Mn, postulating that supplementing male mice with E2 during juvenile development would attenuate neuroinflammatory changes associated with glial activation, including expression of inducible nitric oxide synthase (NOS2) and neuronal protein nitration. Juvenile NF-κB-EGFP mice were separated in groups composed of females, males, and males surgically implanted with Silastic capsules containing 25 μg of 17-β-estradiol (E2) or vehicle control. Mice were then treated with 0 or 100 mg/Kg MnCl(2) by intragastric gavage from postnatal days 21-34. Manganese treatment caused alterations in levels of striatal dopamine, as well as increases in NF-κB reporter activity and NOS2 expression in both microglia and astrocytes that were prevented by supplementation with E2. E2 also decreased neuronal protein nitration in Mn-treated mice and inhibited apoptosis in striatal neurons cocultured with Mn-treated astrocytes in vitro. These data indicate that E2 protects against Mn-induced neuroinflammation in developing mice and that NF-κB is an important regulator of neuroinflammatory gene expression in glia associated with nitrosative stress in the basal ganglia during Mn exposure.

Medical Subject Headings

Animals; Apoptosis; Astrocytes (metabolism); Cells, Cultured; Coculture Techniques; Dopamine (metabolism); Estradiol (blood, pharmacology); Female; Fluorescent Antibody Technique; Gene Expression Regulation; Genes, Reporter; Green Fluorescent Proteins (metabolism); Male; Manganese (toxicity); Manganese Poisoning (pathology); Mice; Mice, Transgenic; Microglia (metabolism); Models, Animal; NF-kappa B (genetics, metabolism); Neurodegenerative Diseases (chemically induced); Neurons (metabolism, pathology); Nitric Oxide Synthase Type II (genetics, metabolism); RNA, Messenger (genetics, metabolism); Sensitivity and Specificity

Publication Date

7-1-2011

Publication Title

Toxicological sciences : an official journal of the Society of Toxicology

E-ISSN

1096-0929

Volume

122

Issue

1

First Page

121

Last Page

33

PubMed ID

21512103

Digital Object Identifier (DOI)

10.1093/toxsci/kfr091

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