Evidence linking cadmium and/or lead exposure to immunomodulatory effects in mammals based upon an adverse outcome pathways approach, and research perspectives

For decades, studies have shown how exposure to non-essential trace metals such as lead (Pb) and cadmium (Cd) largely impact global wildlife. Ecoimmunotoxicology has emerged in the past two decades and focuses on the effects of pollutants on the immune system of free-ranging organisms. Adverse outcome pathways (AOPs) represent a conceptual approach to explore the mechanistic linkage between a molecular initiating event and adverse outcomes, potentially at all biological levels of organisation. The present paper proposes putative AOPs related to the effects of Cd, Pb, and the mixture Cd-Pb, on the immune system of mammals to address future questions in ecoimmunotoxicology. Molecular Initiating Events for both metals relate to entrance in cells through Ca²⁺ channels or bond to cell surfaces. Exposure to Cd, Pb and Cd-Pb share several similar Key Events (KEs), primarily an increase of oxidative stress (OS) in immune cells through production of reactive oxygen species. For both metals and the mixture, OS affects mitochondrial membranes, and induces apoptosis, ultimately decreasing immune cell number. Both metals affect innate immune system through nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) inflammatory signalling pathways, leading to an upregulation of inflammatory markers and mediators. Adaptive immune system is also affected by the exposure to both metals though a decrease of CD4+/CD8+ ratio, a decrease of MHCII, an inactivation of T_H1 and T_H2 response, and an inhibition of the humoral response mediated by various Ig. Mixture effects of Cd-Pb are less documented resulting in a more speculative AOP, but potential synergic and antagonistic effects were identified. According to our AOPs, further research in ecoimmunotoxicology of metals in free-ranging mammals should focus on KEs related to NF-κB/MAPK inflammatory signalling pathways, changes in CD4+/CD8+ ratio and MHCII complexes, and on AOs related to auto-immune disorders and on the effective increase of infection rate, particularly in case of exposure to metal mixtures.