The sales of agricultural insecticides have steadily risen in the last 20 years and the use of fungicides have skyrocketed in the last decade. Unfortunately, direct assessments of children's developmental toxicity in relation to commonly used fungicides such as Azoles or Quinone Outside Inhibitors (QoI) are unavailable because methods for their quantification in bio-specimens have only recently been developed. In experimental studies, exposures QoI fungicides, resulted in epigenetic changes related to neuro-inflammation, and higher levels of free-radicals. Azoles, another heavily used fungicide class, have also been linked with liver inflammation and toxicity in-vitro. Azole fungicides share the same structure as azole antifungals used in clinical practice, which are associated with elevations of liver enzymes in up to 20% of patients. Cholinesterase inhibitor insecticide exposures have been associated with short- and long-lasting neurobehavioral/cognitive delays in children associated. Whether continuing exposures to organophosphates or other insecticides such as neonicotinoids or pyrethroids can affect cognition in adolescence is unclear. We propose to conduct a follow-up investigation of adolescent participants (ages 16-21 y, n=535) of the Secondary Pesticide Exposure among Children and Adolescents (ESPINA) study in 2020. This NIH-funded study has examined participants in Pedro Moncayo County, Ecuador since 2008. Pedro Moncayo has one of the highest concentrations of flower plantations in the Americas. The production of flowers involves a disproportionately high use of fungicides. We plan to assess the ongoing and long-term associations of pesticide exposures with neurocognition, and inflammatory markers (systemic, neuro and liver). To our knowledge, this will be the first epidemiologic study of children/adolescents to evaluate health outcomes in relation to fungicide and neonicotinoid exposures. This prospective study capitalizes on existing blood measurements of insecticides in 2016 and acetylcholinesterase in 2008 and 2016.
The specific aims are to test the following hypotheses: Urinary metabolites of insecticides in 2016 and 2020 (organophosphates, neonicotinoids, pyrethroids) and fungicides (Azoles, QoI) in 2016 are associated with: 1) higher subclinical markers of systemic and neuro inflammation (CRP, TNF, IL-6, sICAM-1, sVCAM-1, MCP-1, sCD14, sCD163); 2) Pesticides, particularly azole fungicides are associated with subclinical increases in liver inflammation markers: transaminases (AST and ALT) and cytokeratin 18. We will test concurrent and prospective associations with all inflammation markers in 2016-2018; 3) lower neur0-cognitive performance in adolescence. We will test longitudinal associations of fungicides and insecticides with neurocognitive performance, and will contrast such findings across pesticides to evaluate neurotoxic potencies. 4) As an exploratory aim: we will assess mediating or modifying effects of inflammation on pesticide-induced impaired neurobehavioral performance.
This investigation will assess concurrent and long-term associations of pesticide exposures with systemic and liver inflammatory markers, and cognitive performance as part of a 12-year follow-up of the ESPINA study, a cohort of children living in agricultural communities in Ecuador. The proposed work will be the first investigation to assess, contrast and account for effects of both insecticides and fungicides (measured in urine) on children's health. Findings from this research will advance the current field of environmental health and inform future risk assessments and disease prevention programs in children and adolescents.