Unique transcriptomic responses of rat and human alveolar macrophages in an in vitro model of overload with TiO and carbon black.

Abstract

Chronic inhalation of titanium dioxide or carbon black can lead, at high exposure, to lung overload, and can induce chronic inflammation and lung cancer in rats. Whether this rat adverse response is predictive for humans has been questioned for more than 40 years. Currently, these particles are conservatively considered as possible human carcinogens. To clarify the mechanisms of the adverse rat response to lung overload and its human relevance. Primary rat and human alveolar macrophages were exposed in vitro to control, non-overload or overload doses of titanium dioxide (P25) or carbon black (Printex 90) particles, and their activation profile was examined by untargeted transcriptomics. Rat macrophages were largely the most responsive to particle overload. In particular, eighteen genes were identified as robust markers of P25 and Printex 90 overload in rat cells. The known functions of these genes can be related to the potential mechanisms of the adverse outcomes recorded in rats in vivo. Most of these 18 genes were similarly modulated in human macrophages, but with a markedly lower magnitude. In addition, a 16 gene signature was observed upon overload in human macrophages, but not in rat macrophages. These findings provide insights into the mechanisms of lung overload and inflammation in rats, and highlight similarities and differences in transcriptomic responses of rat and human alveolar macrophages