Epidemiological and case study reports in children have provided compelling evidence for significant neurobehavioral deficits associated with elevated environmental and dietary manganese (Mn) exposure. However, these studies have not established a causal relationship between Mn exposure and neurobehavioral deficits, nor have they provided a detailed understanding of the specific nature of the cognitive deficits (i.e., learning, attention, emotionality, etc.), or underlying neurochemical alterations.
Aim 1 will determine whether pre-weaning or continuous postnatal Mn exposure produces neurobehavioral deficits in young adults, using a rodent model of Mn neurotoxicity.
Aim II will explore the molecular and neurochemical mechanisms underlying the cognitive deficits induced by pre-weaning or continuous postnatal Mn exposure.
Aim III will determine the relationship of pre-weaning or continuous postnatal Mn exposures with biological markers of exposure, and the extent that these exposure biomarkers are associated with neurobehavioral and neurochemical alterations. We will test the overarching hypotheses that (1) neonatal Mn exposure causes lasting dysfunction in various aspects of cognitive (i.e., learning, memory, attention and/or inhibitory control) and affective (arousal and/or emotion) functioning, and (2) that these changes are linked to developmental alterations in dopaminergic and glutamatergic systems in brain regions which subserve these functions (i.e., the prefrontal cortex, striatum, and hippocampus). We will measure cellular and neurochemical parameters of dopaminergic and glutamatergic system function by microdialysis/biosensor, receptor binding, and immunohistochemistry in the same animals that underwent cognitive testing, in order to provide information about Mn-induced changes in systems that subserve these behavioral functions, and to determine whether one or more of these neural changes correlate with behavioral deficits. Further, we will directly test whether alteration of the dopaminergic system due to Mn exposure plays a role in the resulting behavioral deficits by determining whether Mn exposure alters the dose- response relationship of methylphenidate (Ritalin), a dopamine transporter (DAT) inhibitor, and whether the drug alleviates behavioral deficits due to Mn exposure. These studies will be the most comprehensive assessments to date on the neurological consequences of early life exposure to levels of manganese that infants and children are likely to encounter in their environment. This knowledge will inform public health policies and guidelines on suitable levels of Mn exposure to children.

Public Health Relevance

The proposed studies will address a significant gap in our understanding of the health risks posed by elevated manganese exposure in children by defining in detail the link between early life or continuous postnatal manganese exposure and lasting cognitive deficits, the neurochemical alterations underlying those deficits, and biomarkers that best predict exposure and effects, using a rodent model of childhood Mn exposure. These studies will be the most comprehensive assessments to date on the neurological consequences of early life exposure to levels of manganese that infants and children are likely to encounter in their environment. This knowledge will inform public health policies and guidelines on suitable levels of Mn exposure to children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES018990-05
Application #
8628833
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (03))
Program Officer
Hollander, Jonathan
Project Start
2010-05-06
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$295,594
Indirect Cost
$37,978
Name
University of California Santa Cruz
Department
Public Health & Prev Medicine
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Beaudin, Stephane A; Nisam, Sean; Smith, Donald R (2013) Early life versus lifelong oral manganese exposure differently impairs skilled forelimb performance in adult rats. Neurotoxicol Teratol 38:36-45
Masuda, Melisa; Braun-Sommargren, Michelle; Crooks, Dan et al. (2013) Golgi phosphoprotein 4 (GPP130) is a sensitive and selective cellular target of manganese exposure. Synapse 67:205-15
Eastman, Rachel R; Jursa, Tom P; Benedetti, Chiara et al. (2013) Hair as a biomarker of environmental manganese exposure. Environ Sci Technol 47:1629-37
Kern, Cynthia H; Smith, Donald R (2011) Preweaning Mn exposure leads to prolonged astrocyte activation and lasting effects on the dopaminergic system in adult male rats. Synapse 65:532-44