Project Summary/Abstract
Adolescent brain development is sensitive to exposures and has impacts on neurobehavioral functioning.
Insecticide exposure may impact executive and attentional brain circuits which mature during adolescence due
to pubertal hormonal influences and these changes may manifest as ADHD-related symptoms. There are gaps
in knowledge about how insecticide exposure affects the adolescent brain, when neurobehavioral
vulnerability can undermine lifelong relationships, economic attainment, and overall health.
While most general populations, including adolescents, are exposed to low levels of insecticides through non-
agricultural uses and consuming fruits and vegetables, occupational populations are known to have substantially
higher levels of exposure. Therefore, we have worked extensively with a cohort of Egyptian adolescent pesticide-
applicators who are occupationally exposed to insecticides (a-cypermethrin and chlorpyrifos). Increased ADHD
symptoms and altered neurobehavioral performance in this cohort correlate with a-cypermethrin and chlorpyrifos
toxicological burden. However, moderators and mechanisms underlying these associations remain undefined.
Our pilot data indicate that combined adolescent exposure leads to altered neurobehavior and dopamine
systems in the brain in mice. The effects in pesticide applicators are present many months after exposure. The
epigenome is a potential mediator of the relationship between exposures and long-term neurobehavioral effects
due to its unique sensitivity to the environment and potential to regulate gene expression throughout the lifespan.
Our overall hypothesis is that combined adolescent insecticide exposures impact neurobehavioral
outcomes. We additionally hypothesize that effects are modified by testosterone level, act via oxidative stress
in dopamine neurons, and have a long-term trajectory via epigenetic change. We will test these with three
synergistic aims joining human investigation and animal mechanistic assessments with translation
between them, facilitated by a transdisciplinary investigator team, novel approaches, and a well laid-out
consortium plan. In Aim 1, we will leverage stored samples and data from adolescent pesticide-applicators to
quantify the neurobehavioral impact of combined versus single insecticide exposures, assessing the high-
reward, high-risk hypothesis that pesticide-applicator testosterone level moderates this association. In
Aim 2, we will model these adolescent insecticide exposures in mice to examine causality and use
manipulations to test oxidative stress as a mechanism and testosterone level as a moderator of effects. Cell
culture studies will provide convergent results for the role of dopamine neurons. In Aim 3, we will examine DNA
methylation across both human and mouse samples collected after completion of peak insecticide exposure, to
examine the potential epigenetic mechanisms translationally of long-term neurobehavioral risk. This work
is the first step to accelerate translation of scientific research into meaningful improvements in human health—
namely improving insecticide exposure policies and developing interventions to protect youth.
