Fetal exposure to methylmercury (MeHg) has long-lasting effects on sensory-motor function, schedule-controlled behavior, learning (not memory) and sensitivity to certain behaviorally active drugs. Human and animal studies now associate developmental or adult MeHg exposure with age-related declines in certain behavioral functions. Nutritional influences also modify mercury's neurotoxicity, although how these interact through the lifespan is not well understood. This is important both mechanistically and because of concerns that a low RfD for MeHg would decrease consumption of fish, a source of selenium and n-3 fatty acids, especially docosahexanoic acid (DHA). In previous work, rats on a chow diet consuming 40 or 500 mg/kg/day Hg (as MeHg) showed age- and dose-related decrements on high-rate operant behavior, retarded learning, and altered sensitivity to amphetamine and pentobarbital. Proposed studies extend these observations by examining age and diet as modifiers of MeHg's neurobehavioral toxicity. High-rate operant behavior will be examined using a refined procedure (targeted percentile schedule) that maintains high response rates but without lowering reinforcement rates if behavior deteriorates. Concurrent schedule performance in transition, which now can be conducted in single sessions, will be the measure of learning. Fixed-interval (FI) schedule performance will be examined per se and as a baseline for drug challenges. Female rats will start one of three diets (modified semipurified, DHA-enriched, Se-enriched) for two weeks, then MeHg exposure (0. 0.5, or 5 ppm in drinking water) for two weeks, then they will be mated. Maternal rats will continue the diets and mercury exposure to 30 months of age, and their behavior examined under a targeted percentile schedule of reinforcement. During this time they will receive selected drug challenges. At death mercury levels in blood and brain, Se (in the Se cohort) and DHA in the DHA cohort) will be examined. Offspring will be maintained on the different diets and used as follows: 1) Hg and Se or FA profile determination PN1; 2) FI schedule performance in transition with drug challenges: 3) Targeted percentile schdule performance, and 4) Concurrent schedule performance in transition with drug challenges. Items 2-4 will be conducted as adults and 3-4 to 30 months of age. At death Hg and either Se or FA profiles will be determined, depending on the cohort.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010865-03
Application #
6635521
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Kirshner, Annette G
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
3
Fiscal Year
2003
Total Cost
$357,500
Indirect Cost
Name
Auburn University at Auburn
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
066470972
City
Auburn University
State
AL
Country
United States
Zip Code
36849
Newland, M Christopher; Reed, Miranda N; Rasmussen, Erin (2015) A hypothesis about how early developmental methylmercury exposure disrupts behavior in adulthood. Behav Processes 114:41-51
Newland, M Christopher; Hoffman, Daniel J; Heath, John C et al. (2013) Response inhibition is impaired by developmental methylmercury exposure: acquisition of low-rate lever-pressing. Behav Brain Res 253:196-205
Heath, John C; Banna, Kelly M; Reed, Miranda N et al. (2010) Dietary selenium protects against selected signs of aging and methylmercury exposure. Neurotoxicology 31:169-79
Reed, Miranda N; Newland, M Christopher (2009) Gestational methylmercury exposure selectively increases the sensitivity of operant behavior to cocaine. Behav Neurosci 123:408-17
Newland, M Christopher; Paletz, Elliott M; Reed, Miranda N (2008) Methylmercury and nutrition: adult effects of fetal exposure in experimental models. Neurotoxicology 29:783-801
Reed, Miranda N; Banna, Kelly M; Donlin, Wendy D et al. (2008) Effects of gestational exposure to methylmercury and dietary selenium on reinforcement efficacy in adulthood. Neurotoxicol Teratol 30:29-37
Paletz, Elliott M; Day, Jeremy J; Craig-Schmidt, Margaret C et al. (2007) Spatial and visual discrimination reversals in adult and geriatric rats exposed during gestation to methylmercury and n-3 polyunsaturated fatty acids. Neurotoxicology 28:707-19
Reed, Miranda N; Newland, M Christopher (2007) Prenatal methylmercury exposure increases responding under clocked and unclocked fixed interval schedules of reinforcement. Neurotoxicol Teratol 29:492-502
Paletz, Elliott M; Craig-Schmidt, Margaret C; Newland, M Christopher (2006) Gestational exposure to methylmercury and n-3 fatty acids: effects on high- and low-rate operant behavior in adulthood. Neurotoxicol Teratol 28:59-73
Newland, M Christopher; Reed, Miranda N; LeBlanc, Alain et al. (2006) Brain and blood mercury and selenium after chronic and developmental exposure to methylmercury. Neurotoxicology 27:710-20

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