RATIONALE OF THE STUDY Chronic obstructive pulmonary disease (COPD) is a disease of increasing incidence characterized by progressive airflow limitation and inflammation. COPD risk is strongly related to tobacco smoking, but environmental and genetic factors are also involved in its pathogenesis. There is increasing evidence that adverse exposures (cigarette smoke, pollution, nanoparticles (NP)) occurring during foetal and early infant life can impair the development of the lungs and may finally increase risks of COPD at adulthood. Using a mouse model, we have recently shown that respiratory exposure of pregnant mice to metal NP leads to alterations in lung morphology in pups, with a persistent alveolar airspace enlargement. In order to determine if such modifications represent a susceptibility factor to develop a COPD-like phenotype in later life, we exposed the progeny to cigarette smoke and analysed the morphology of the lungs. METHODS Three metal nanoparticles were used in the study: Cerium oxide, Silver and Gold (diameter 15 to 30 nm). We performed weekly non-surgical intratracheal instillation of 100µg nanoparticles on C57BL/6 pregnant mice during the entire course of gestation. At the age of two months, the progeny was exposed to cigarette smoke for 7 and 12 weeks. The lung morphology was analysed at different stages of alveolar development (E17.5, P23 and P60) and after cigarette smoke exposure. RESULTS The number of pups per pregnant mother, as well as their weight was similar between the 4 experimental groups. Respiratory exposure of pregnant mice to metal nanoparticles induce persistent lung morphological abnormalities in the progeny, demonstrated by enlargement of the alveolar airspace already at P23 and which remains at P60. The mean linear intercept (MLI), of 151.3 +/- 7.2 µm in controls lungs, is increased to 171.8 +/- 8.2 µm with Silver, 166.0 +/-3.9 with Cerium and 166.4 +/-3.9 with Gold NP (p<0.005). Cigarette smoke exposure induces an alveolar enlargement in control lungs (MLI = 172.8 +/- 9.3 µm), which is increased in all the NP groups, with MLI of 191.7 +/- 6.5 with Silver, 190.9 +/- 5.8 with Cerium and 191.3 +/- 7.6 with Gold NP (p<0.005). The biological mechanisms underlying these effects are currently under investigation. CONCLUSIONS These findings suggest that early exposure to metal nanoparticles during the critical time-window of pregnancy could represent a risk factor to develop COPD in adulthoo