Pyrethroid pesticides are the predominant pesticide for household use along with their uses in agriculture and public health. Significant levels of pyrethroid metabolites have been found in the urine of pregnant women and in preschool children. This raises concern that developmental exposure to pyrethroids may cause damage to the developing nervous system. Recent data from the Richardson laboratory demonstrate that mice developmentally exposed to low levels of the pyrethroid pesticide deltamethrin exhibit symptoms similar to those observed in children with Attention Deficit Hyperactivity Disorder (ADHD), including elevated dopamine transporter (DAT) levels, hyperactivity and impulsive-like behavior, amelioration of the behavioral deficits by methylphenidate (Ritalin), 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. Furthermore, we now have epidemiological evidence that children with measurable levels of a deltamethrin metabolite in their urine are more than twice as likely to be diagnosed with ADHD. Therefore, it is imperative to determine whether pyrethroid pesticides other than deltamethrin cause similar effects and the mechanism(s) by which pyrethroids alter the developing brain. There are currently 16 pyrethroid pesticides registered for use in the United States and examination of the developmental effects of these compounds using the mouse model would be prohibitively expensive and time-consuming. We propose to use the zebrafish (Danio rerio) as a model to assess the risk of developmental exposure to pyrethroid pesticides and to investigate the mechanisms of pyrethroid alterations in dopamine signaling. The zebrafish model system is ideal for these studies as they exhibit significant genetic and physiological similarity to mammals, are suited for moderate to high-throughput screening, and allow for direct exposure of the embryo. Our data demonstrate that developmental exposure to deltamethrin has similar effects in zebrafish as observed in the mouse model, including increased expression of the DAT, and increased activity. Our preliminary data also demonstrate that the effects of pyrethroids on the developing embryo differ between various pyrethroids. Here, we propose 3 Specific Aims to characterize the neurochemical and behavioral effects of developmental pyrethroid exposure, determine molecular mechanisms by which pyrethroids affect the dopamine system, and to screen other pyrethroids for their ability to reproduce these effects. These studies will provide insight into mechanisms by which developmental pyrethroid exposure alters the dopamine system and how these alterations lead to behavioral dysfunction. Development of a zebrafish model of ADHD would allow for high-throughput studies to screen for pesticide toxicity, explore ADHD pathophysiology in addition to screening for therapeutic compounds to treat ADHD.
In the past decade, there has been increasing concern that children are more sensitive to the adverse effects of pesticides. With the phase out of organophosphate use for household applications, pyrethroid pesticides have become the predominant pesticide used for household applications and have extensive uses in agriculture and public health as well. Data from the human population indicate that exposure to pyrethroid pesticides is associated with Attention-Deficit Hyperactivity Disorder (ADHD). ADHD is rapidly becoming a significant public health issue, as a recent report found that approximately 7% of children aged 5 to 17 in the United States have been diagnosed with ADHD (NCHS, 2002). The goal of this proposal is to investigate the effect of embryonic exposure to pyrethroids on later effects on gene expression and hyperactivity using the zebrafish model. The data generated by these studies will provide a novel model for studying pesticide toxicity, as well as identify key targets for potential therapies for ADHD.
| 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 |
