52 - Oxidizing Nano Particles (Smog) Induce Protective Levels of Proteasome via the Nrf2 Signal Transduction Pathway in Young but Not Old Female Mice

Abstract

Environmental toxicants can act as accelerators of protein damage, with excess accumulation of protein aggregates promoting the aging process. Fortunately, organisms rely upon the adaptive homeostatic response to mitigate damage accumulation. The leading transcriptional activator associated with adaptation to oxidative stress is Nrf2, which upon nuclear translocation, can upregulate a plethora of stress responsive proteins, including the 20S proteasome. To understand the impact of environmental toxicants upon the adaptive homeostatic response in a mammalian mouse model, young (6 month) and middle-aged (21 month) female mice were exposed to either filtered air or reaerosolized vehicular-derived nanoparticulate (nPM) matter. Our findings suggest age and nPM exposure to impact the inducibility of the adaptive homeostatic response. Exposure to nPM in young tissue caused an adaptive increase in Nrf2 and its target genes. Conversely, nPM exposure in middle age, resulted in the lack of Nrf2-induction and increase in Nrf2 transcriptional inhibitors, Bach1 and c-Myc, accompanied with a parallel loss in adaptability of Nrf2-responsive genes, including the proteasome. These findings match a similar age-associated trend found in nPM-exposed male mice. More importantly, these results demonstrate the conserved trend of the age-dependent loss of the adaptive response , first demonstrated in the nematode worm and fruit fly, and now, in a mammalian mouse model.