Neurodevelopmental Exposure to Pyrethroid Insecticides and Stress Affects Dopaminergic Pathways Relevant to Attention-Deficit Hyperactivity Disorder Öffentlichkeit
Vester, Aimee (Spring 2019)
Abstract
Attention-Deficit Hyperactivity Disorder (ADHD) affects 7% of children and presents with inattention, hyperactivity, and impulsivity. Most children are treated with stimulants, but long-term use is associated with stunted growth, cognitive effects, and decreased quality of life. Understanding ADHD etiopathogenesis is thus imperative. Studies suggest altered dopamine signaling plays a major role in ADHD. Known dopaminergic genetic factors contribute to ADHD, but do not wholly explain its pathogenesis. This indicates a role for environmental risk factors.
Independently, pyrethroid insecticides and chronic stress are associated with dopaminergic dysfunction and ADHD. Pyrethroids are used residentially and agriculturally, and indoor pyrethroid use is elevated in poor housing conditions. This increases the vulnerability of children living in poorer housing, who are often of low socioeconomic status (SES), to pyrethroids and subsequent neurodevelopmental alterations. Children of low SES also experience higher levels of chronic stress and are at greater risk of developing ADHD. Chronic stress alters key dopaminergic components, and thus may also contribute to dopamine-related ADHD pathophysiology.
We hypothesized these two exposures together would lead to synergistic effects in the dopamine system and ADHD. To test this, we assessed dopaminergic consequences of combined exposure to deltamethrin and the major stress hormone, corticosterone, in a neurodevelopmental mouse model. In males exposed to deltamethrin, we observed decreased midbrain Pitx3 RNA expression, decreased tyrosine hydroxylase in the frontal cortex, impaired dopamine uptake, and hyperactivity. We also observed hypermethylation at a CpG site of the Nr3c1 promoter in males exposed to deltamethrin and corticosterone. Thus, we saw sex-specific dopaminergic alterations that contribute to our understanding of dopaminergic neurodevelopment and ADHD.
Next, we assessed the relationship between pyrethroids, chronic stress, and ADHD in the National Health and Nutrition Examination Survey (NHANES). We developed a pediatric model of allostatic load to better parameterize sociodemographic and biological stressors and demonstrated significant multiplicative interaction between urinary pyrethroid metabolites and allostatic load in the prevalence of ADHD. This research reflects exposure scenarios that target dopaminergic systems and could disproportionately affect low SES populations. Understanding these mechanisms can help inform initiatives to reduce the disease burden of ADHD.
Table of Contents
CHAPTER 1: INTRODUCTION.. 1
ATTENTION-DEFICIT HYPERACTIVITY DISORDER.. 2
THE DOPAMINE SYSTEM.. 3
DOPAMINE SYNTHESIS AND METABOLISM... 4
DOPAMINE TRANSPORT AND SIGNALING.. 4
DEVELOPMENT OF THE DOPAMINE SYSTEM.. 8
ENVIRONMENTAL EXPOSURES IN ADHD.. 11
PYRETHROID INSECTICIDES. 12
NEURONAL EFFECTS OF PYRETHROID EXPOSURE.. 14
DOPAMINERGIC EFFECTS OF PYRETHROIDS IN ADULTHOOD.. 15
DOPAMINERGIC EFFECTS OF PYRETHROIDS IN DEVELOPMENT.. 15
SOCIOECONOMIC STATUS AND PSYCHOSOCIAL STRESS. 16
THE HPA AXIS AND STRESS RESPONSE. 17
STRESS AND THE DOPAMINE SYSTEM... 21
EPIGENETICS AND ENVIRONMENTAL EXPOSURE. 22
SUMMARY.. 24
CHAPTER 2: A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure: Deltamethrin Causes Dopaminergic Alterations Independent of Corticosterone. 26
ABSTRACT. 27
INTRODUCTION.. 28
METHODS. 32
RESULTS. 40
DISCUSSION.. 61
ACKNOWLEDGEMENTS. 70
SUPPLEMENTAL MATERIALS. 70
CHAPTER 3: Combined neurodevelopmental exposure to deltamethrin and corticosterone is associated with Nr3c1 hypermethylation in the midbrain of male mice. 71
ABSTRACT. 72
INTRODUCTION.. 74
METHODS. 77
RESULTS. 84
DISCUSSION.. 90
ACKNOWLEDGEMENTS. 95
SUPPLEMENTAL MATERIALS. 96
CHAPTER 4: Urinary pyrethroid insecticide metabolites and allostatic load are associated with increased ADHD prevalence in children ages 6-18 years in NHANES. 107
ABSTRACT. 108
INTRODUCTION.. 108
METHODS. 112
RESULTS. 120
DISCUSSION.. 132
ACKNOWLEDGEMENTS. 135
CHAPTER 5: DISCUSSION.. 136
SUMMARY OF FINDINGS. 137
FUTURE DIRECTIONS. 140
REFERENCES 144
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