Integrating experimental and physiologically based pharmacokinetic modeling approaches to evaluate neurotoxicity of the herbicide atrazine across the lifespan
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Atrazine (ATR) is a widely used chlorotriazine herbicide. Available experimental evidence and computational tools are insufficient for proper assessment of ATR’s risk to human health. This dissertation project aimed to determine neurotoxicity of ATR overexposure during adulthood, development, or in vitro, and to create physiologically based pharmacokinetic (PBPK) models for ATR across the lifespan in rodents. In adult male C57BL/6 mice, short-term oral ATR exposure (5-250 mg/kg) caused dose-dependent reduced performance in a novel object recognition test (NOR), open field hypoactivity and increased swimming time in a forced swim test at higher doses; the latter effects were accompanied with altered dopamine and serotonin homeostasis in the striatum and prefrontal cortex. Low-level drinking water (DW) ATR exposure (3 mg/L) during gestation and lactation resulted in hyperactivity and decreased NOR performance in mouse dams, hyperactivity in male and female juvenile offspring, decreased swimming time in male juveniles, increased marble burying in female juveniles, and decreased NOR performance in female adults. Neurochemically, DW ATR exposure increased striatal dopamine in dams and juvenile offspring. In vitro exposure (24-48 h; 12-300 µM) to ATR or its main metabolite didealkylatrazine (DACT) affected morphological differentiation of N27 dopaminergic cells with ATR mainly targeting soma enlargement (dose-dependent effect) and DACT decreasing neurite outgrowth (high-dose effect). A PBPK model for ATR and its metabolites desethylatrazine, desisopropylatrazine and DACT was developed in adult male mice and then extrapolated to rats. This adult rodent model and recent experimental data were the foundation for a subsequent developmental PBPK model that accurately described ATR’s kinetic behavior during fetal, neonatal, pregnant and lactating stages in rats. Model simulations aligned well with experimental data, including with a new pharmacokinetic study conducted with pregnant mice orally exposed to ATR, validating the cross-species extrapolation of the gestational model. In conclusion, ATR overexposure affects multiple behavioral domains and perturbs brain dopamine and serotonin homeostasis, with some effects on the offspring being sex-specific. ATR- and/or DACT-induced neuronal differentiation disruption may contribute to the observed developmental neurotoxicity. The newly developed PBPK models can be used in brain dosimetry predictions and, together with the experimental data, may improve ATR’s risk assessment.