Effects of Ozone on Sickness and Depressive-like Behavioral and Biochemical Phenotypes and Their Regulation by Serum Amyloid A in Mice.

Ozone (O) is an air pollutant that primarily damages the lungs, but growing evidence supports the idea that O also harms the brain; acute exposure to O has been linked to central nervous system (CNS) symptoms such as depressed mood and sickness behaviors. However, the mechanisms by which O inhalation causes neurobehavioral changes are limited. One hypothesis is that factors in the circulation bridge communication between the lungs and brain following O exposure. In this study, our goals were to characterize neurobehavioral endpoints of O exposure as they relate to markers of systemic and pulmonary inflammation, with a particular focus on serum amyloid A (SAA) and kynurenine as candidate mediators of O behavioral effects. We evaluated O-induced dose-, time- and sex-dependent changes in pulmonary inflammation, circulating SAA and kynurenine and its metabolic enzymes, and sickness and depressive-like behaviors in Balb/c and CD-1 mice. We found that 3 parts per million (ppm) O, but not 2 or 1 ppm O, increased circulating SAA and lung inflammation, which were resolved by 48 h and was worse in females. We also found that indoleamine 2,3-dioxygenase () mRNA expression was increased in the brain and spleen 24 h after 3 ppm O and that kynurenine was increased in blood. Sickness and depressive-like behaviors were observed at all O doses (1-3 ppm), suggesting that behavioral responses to O can occur independently of increased SAA or neutrophils in the lungs. Using SAA knockout mice, we found that SAA did not contribute to O-induced pulmonary damage or inflammation, systemic increases in kynurenine post-O, or depressive-like behavior but did contribute to weight loss. Together, these findings indicate that acute O exposure induces transient symptoms of sickness and depressive-like behaviors that may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. SAA does not appear to contribute to pulmonary inflammation induced by O, although it may contribute to other aspects of sickness behavior, as reflected by a modest effect on weight loss.