Background Attention Deficit Hyperactivity Disorder (ADHD) is an increasingly common neurobehavioral disorder diagnosed in childhood, with enormous costs to the individuals affected, their families, and to society. In the US, direct and indirect costs of ADHD are estimated to be between $143 billion and $266 billion a year. The etiology of ADHD is not understood, although measures of oxidative stress and lipid metabolism are among potential biomarkers of risk. Exposure to endocrine disrupting chemicals (EDCs), such as phthalates, may also play a role, as urinary phthalate concentrations have been associated with increased ADHD behaviors, such as inattention, impulsivity, and hyperactivity in previous cross-sectional studies.
Preliminary Findings We recently found that within the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort, measures of phthalate exposure during both in utero development and in adolescence were associated with poorer scores on the Connors Continuous Performance Test 3rd edition (CPT-3), a widely used measure of ADHD behaviors, at 9-18 years of age. Urinary phthalate metabolite levels have also been associated with increased 8-isoprostane, a marker of lipid oxidation, with potential impact on tissue phospholipids and neurotransmission. In addition, preliminary analyses of untargeted metabolomics data collected from the ELEMENT cohort at 8-14 years of age showed that prenatal phthalate exposure was also associated with a number of unknown and known metabolites, including phospholipids, fatty acids, and testosterone.
Premise of the Proposed Study Our preliminary findings suggest that in addition to the well-established anti-androgenic activity of phthalates, in utero phthalate exposure may also affect both long-term neurobehavioral function and lipid homeostasis. Interestingly, children and adults with ADHD have been found to have altered lipid profiles, particularly changes in polyunsaturated fatty acids (PUFAs), compared to normally functioning controls. Lipids are crucial to neurodevelopment, as well as maintaining neurological function throughout adulthood. Based on these findings, we hypothesize that prenatal and adolescent phthalate exposure may affect ADHD symptoms via oxidative stress and/or disruption of lipid homeostasis.
Specific Aims We have designed the following aims, which leverage existing untargeted metabolomics and urinary phthalate data collected from ELEMENT mothers and adolescents through the University of Michigan Children’s Environmental Health Center (UM-CEHC), to test this hypothesis. In Aim 1, we will assess associations of prenatal and adolescent urinary phthalate metabolite concentrations with recently acquired high-dimensional untargeted metabolomic data measured at 9-18 years of age. In Aim 2, we will then assess associations between the high-dimensional untargeted metabolomic data and scores on the CPT-3, which measures attention and impulsivity, at 9-18 years of age. In Aim 3, we will assess metabolites identified in Aims 1 and 2 as mediators of associations between prenatal and adolescent urinary phthalate metabolite concentrations and CPT scores at 9-18 years of age.
Expected Deliverables This work will provide insight into the mechanisms by which exposures may induce ADHD symptoms, as well as preliminary data for future external grant applications. As this MCubed project utilizes already existing data and expertise in high-dimensional mediation analysis, if awarded, it would allow us to fund graduate student(s) with interest and analytic skills in high-dimensional metabolomics analysis and the ELEMENT cohort to help us complete these aims. Publications and future NIH grant applications will be deliverables from this project.