? ? Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder characterized by core features of impulsivity, hyperactivity, and attention deficits. ADHD is estimated to affect 8-12% of ? school-aged children worldwide. ADHD is a complex disorder with significant genetic contributions. ? However, no single gene has been linked to a significant percentage of cases, suggesting that ? environmental factors or gene-environment interactions may contribute to the etiology or clinical ? manifestation of ADHD. Dopamine transporter (DAT) polymorphisms and elevated expression of the DAT have been observed in ADHD patients, suggesting alterations in DAT levels may contribute to ADHD. Since environmental factors, such as pesticides, have been shown to alter DAT expression, we have hypothesized that in utero pesticide exposure may contribute to the incidence or severity of ADHD. Recent data from this laboratory have demonstrated that the offspring of mice exposed to low levels of the pyrethroid pesticide deltamethrin during development exhibit similar symptoms as observed in children with ADHD, including elevated DAT levels, hyperactivity, a paradoxical calming response to psychostimulants, behavioral deficits, and a male gender-preference of these effects. Importantly, the doses that elicited these effects were at or below the no observable adverse effect level (NOAEL) established by the EPA for deltamethrin. This is particularly notable because the NOAEL used by the EPA when making regulatory decisions on pesticides. Because there has been documented exposure of pregnant women to pyrethroids and pyrethroid use has increased dramatically in the last decade, it may be prudent to evaluate pesticide exposure as a potential risk factor for ADHD. Furthermore, these mice represent a novel animal model to test therapies for ADHD and provide insight into the basic mechanisms underlying this disorder. Here, the investigators propose three Specific Aims to investigate mechanisms underlying the effects of deltamethrin on the dopamine system and characterize the behavioral effects of developmental deltamethrin expsoure. The investigators will then use this information to exploit this novel model to identify molecular targets for therapeutic intervention in ADHD. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES015991-01
Application #
7337586
Study Section
Special Emphasis Panel (ZES1-JAB-C (R1))
Program Officer
Lawler, Cindy P
Project Start
2007-09-01
Project End
2012-06-30
Budget Start
2007-09-01
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$557,721
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Green, Ashley L; Zhan, Le; Eid, Aseel et al. (2017) Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1. Neuropharmacology 125:189-196
Hossain, Muhammad M; Liu, Jason; Richardson, Jason R (2017) Pyrethroid Insecticides Directly Activate Microglia Through Interaction With Voltage-Gated Sodium Channels. Toxicol Sci 155:112-123
Hossain, Muhammad M; DiCicco-Bloom, Emanuel; Richardson, Jason R (2015) Hippocampal ER stress and learning deficits following repeated pyrethroid exposure. Toxicol Sci 143:220-8
Kung, Tiffany S; Richardson, Jason R; Cooper, Keith R et al. (2015) Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish. Toxicol Sci 146:235-43
Wagner-Schuman, Melissa; Richardson, Jason R; Auinger, Peggy et al. (2015) Association of pyrethroid pesticide exposure with attention-deficit/hyperactivity disorder in a nationally representative sample of U.S. children. Environ Health 14:44
Sheleg, Michal; Yochum, Carrie L; Richardson, Jason R et al. (2015) Ephrin-A5 regulates inter-male aggression in mice. Behav Brain Res 286:300-7
Magby, Jason P; Richardson, Jason R (2015) Role of calcium and calpain in the downregulation of voltage-gated sodium channel expression by the pyrethroid pesticide deltamethrin. J Biochem Mol Toxicol 29:129-34
Baker, Angela A; Guo, Grace L; Aleksunes, Lauren M et al. (2015) Isoform-Specific Regulation of Mouse Carboxylesterase Expression and Activity by Prototypical Transcriptional Activators. J Biochem Mol Toxicol 29:545-51
Green, Ashley L; Hossain, Muhammad M; Tee, Siew C et al. (2015) Epigenetic Regulation of Dopamine Transporter mRNA Expression in Human Neuroblastoma Cells. Neurochem Res 40:1372-8
Richardson, Jason R; Taylor, Michele M; Shalat, Stuart L et al. (2015) Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder. FASEB J 29:1960-72

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