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

Ozone (O ₃ ) is an air pollutant that primarily damages the lungs, but growing evidence supports the idea that O ₃ also harms the brain; acute exposure to O ₃ has been linked to central nervous system (CNS) symptoms such as depressed mood and sickness behaviors. However, the mechanisms by which O ₃ inhalation causes neurobehavioral changes are limited. One hypothesis is that factors in the circulation bridge communication between the lungs and brain following O ₃ exposure. In this study, our goals were to characterize neurobehavioral endpoints of O ₃ 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 ₃ behavioral effects. We evaluated O ₃ -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 ₃ , but not 2 or 1 ppm O ₃ , 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 ( Ido1 ) mRNA expression was increased in the brain and spleen 24 h after 3 ppm O ₃ and that kynurenine was increased in blood. Sickness and depressive-like behaviors were observed at all O ₃ doses (1-3 ppm), suggesting that behavioral responses to O ₃ can occur independently of increased SAA or neutrophils in the lungs. Using SAA knockout mice, we found that SAA did not contribute to O ₃ -induced pulmonary damage or inflammation, systemic increases in kynurenine post-O ₃ , or depressive-like behavior but did contribute to weight loss. Together, these findings indicate that acute O ₃ 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 ₃ , although it may contribute to other aspects of sickness behavior, as reflected by a modest effect on weight loss.