摘要
Aim:The purpose of this study was to evaluate sex-biased,maladaptive changes to epigenetic regulation critical for development of neuroimmune crosstalk resulting from an early-life toxicant exposure previously associated with increased susceptibility to later-life neurodegeneration.Methods:An evaluation of early-life gene x environment(GxE)interactions was performed in a mouse model of Alzheimer's disease(Tg)orally exposed to lead acetate(Pb)from postnatal day(PND)5-9.Following exposure,immunohistochemical analysis was used to evaluate hippocampal expression of DAP12,a marker for perinatal microglia related to microglial-mediated postnatal synaptic pruning of neurons.Altered profiles of three microRNAs critical to homeostatic microglia:neuron signaling(miR-34a,miR-124,miR-132)were measured by qRT-PCR.Results:Atypical and deleterious expression patterns in Pb-exposed Tg mice were detected with significant female bias by PND 10.Early exposure to Pb resulted in the upregulation of miR-124,a microRNA involved in microglial quiescence,as well as miR-34a,involved in p53-dependent apoptosis and decreased phagocytosis,by PND 21 and during a period of microglial-mediated synaptic pruning specific to females.In addition,we observed a sustained,imbalanced upregulation of miR-132 in Pb-exposed Tg females as well as decreased expression of DAP12.Conclusion:This study demonstrates the exacerbating effects and early manifestation of GxE interactions in this model.Furthermore,these findings underscore a period of female-specific vulnerability to epigenetic maladaptation during postnatal development,with implications on the faulty later-life adaptability of neuroimmune signaling.Further investigation is warranted to evaluate the persistence and relative contribution of these early influences on the etiopathology of Alzheimer's disease.
基金
This work was supported by the Harriet and John Wooten Laboratory for Alzheimer’s and Neurodegenerative Diseases Research(https://www.ecu.edu/cs-dhs/wootenlab/).The funding body provided access to the 3xTgAD transgenic and wildtype mice used in the study.
