163 - Nano-Particulate Exposure Impacts Proteasome Adaptive Responses in Young and Middle-Aged Female Mice

Abstract

Environmental toxicants contribute to cellular oxidative stress, damaging proteins, and if not removed or neutralized, causing protein oxidation, aggregation, and cross-linking. The time-dependent accumulation of protein-aggregates is a potential underlying contributor to the aging process. By rapidly degrading minimally oxidized intracellular proteins, proteinases such as the 20S Proteasome, the Immunoproteasome, and (inside mitochondria) the Lon protease minimize the extent of protein aggregation and cross-linking. With advancing age, however, the efficiency of these proteinolytic systems declines. Our objective is to understand age-related changes associated with nanoparticulate exposure (representing environmental photochemical smog) by comparing young (3 month) and middle-aged (18 month) female mice. In the present study we have focused on the Proteasome and its transcriptional regulators. Female mice were exposed to either ambient air or re-aerosolized particulate matter (nPM) collected from the 110 Freeway (in Southern California). Both 3 month and 18 month old female mice were exposed for 5 hours a day, 3 days a week, for a total of 10 weeks. Afterwards, heart, liver, and lung tissue was collected and protein expression, activity, and oxidation was assessed. Our results show that that both nPM exposure and age affect Proteasome expression and activity in lung, heart, and liver. In all three tissues, nPM exposure resulted in loss of Proteasome activity, yet expression increased in an age- and nPM-dependent manner. Interestingly, Nrf2, the transcriptional activator of the Proteasome, showed age-related increases, accompanied by age-related increases in the levels of the transcriptional suppressors, Bach1 and c-Myc. Thus our findings indicate that cells may be unable to appropriately degrade non-functional Proteasome, and/or the increase in levels of the transcriptional suppressors, Bach1 and c-Myc limits the generation of new functional Proteasome. This work should lead to a clearer understanding of the effects of pollution on aging, and of the Proteasomes’ specific involvement in the aging process.