Developmental emamectin benzoate exposure alters ontological proteomic signatures in Long Evans rats
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Neurodevelopmental periods are vulnerable to environmental compounds, but there are few adverse outcome pathways (AOP) that detail the key events critical to adverse neurodevelopmental outcomes. AOPs describe a series of biological responses linked by key events, ending in an adverse outcome. We are using proteomic changes produced by xenobiotics to assess molecular alterations which can be applied in the AOP framework. Pregnant Long Evans rats were gavaged with emamectin benzoate (EB; 3.78 mg/kg in 5 mL/kg DI water) or vehicle, from gestational day 6 to postnatal day (PND) 21. Region-specific brain tissues were collected from male and female offspring on PND2, 8, 15, or 22 (one pup/sex/treatment/timepoint). Offspring brain samples were analyzed using Orbitrap LC-MS and the identified proteins were then further processed using Proteome Discover (v 2.4) and Ingenuity Pathway Analysis software. Comparisons of proteomic content were made across the developmental period, examining changes between PND2 and PND22 for each treatment and by sex. Pathway analyses displayed different biological processes between the groups. Female rats treated perinatally with EB had proteomic signatures that implicated inhibition in pathways involved in cognition and synthesis and concentration of ATP which were not indicated in controls. In EB treated males, we observed pathways involved in cognition, learning, and memory to be inhibited, and activation in processes involved in cellular degradation and abnormalities of the cerebral cortex. Top up or downregulated molecules in female EB-treated rats compared with controls included processes such as cell adhesion (increased expression: Clstn1, Fga; decreased: Aqp4), metabolic processes (decreased: Ca4), and cell proliferation (increased: Igf2bp1). Male EB-treated rats exhibited protein alterations involved in signal transduction (increased: Hap1, Dcc; decreased: Ppp1r1b), cell to cell signaling (decreased: Pvalb), stress response (increased: Serpina1), and cytoskeletal activity (decreased Ermn). Additional proteomic analyses of other brain regions are on-going. Overall, we observed an ontological change in the proteomic signature following perinatal EB treatment. Information regarding changes in profiles of proteomic development can serve as key events to map onto AOP frameworks. This is an abstract of a proposed presentation and does not necessarily reflect US EPA policy.