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Mixture effects

Published on 15 January 2021
Thierry Douki & Marie Carrière

Toxicity associated with environmental exposure has always been a major concern in human health. While many studies have been carried out on physical agents alone or on pure chemical compounds, increasing interest is being paid to the problem of co-exposures. It is indeed increasingly clear that the toxic effects of mixtures is not the sum of the effects of each component taken individually. Numerous examples in various fields show that phenomena of inhibition or synergy deflect the toxic impact of simple additivity. This necessary consideration of the complexity of real exposures has led to the notion of exposome. The team is working on this topic for several years. For example, several studies have been devoted to the co-exposure of cells to nanoparticles and DNA damaging agents. A synergistic effect has been observed in several cases.

Another investigated topic in our group is related to atmospheric pollution and in particular the effects of polycyclic aromatic hydrocarbons (PAH). These compounds constitute a wide family of molecules emitted in different proportion depending on the source. We observed that the formation DNA adducts of the vey toxic benzo[a]pyrene was reduced in culture of liver cells when benzo[k]fluoranthene was added but increased with benzo[b]fluoranthene. In lung cells, decrease was observed in both cases. Another interesting observation was made with organic extracts from real atmospheric samples. At constant applied B[a]P concentration, formation of DNA-B[a]P adducts in hepatocytes was stimulated with PAH-rich industrial samples while it decreased for urban samples. This result points to a major role played by the components of the mixture on the biological consequences of the exposure.

Formation of DNA-B[a]P adducts in cultured human cells exposed to B[a]P in the presence of increasing amounts of a second PAH. B[a]P concentration was 1 µM. Result represent the ratio between the level of adduct with pure B[a]P and in the mixture.

Recently, we combined our interest in the effects of chemicals and solar UV radiation in the investigation of the combined exposure of skin to PAH and sunlight. Working both in primary cultures of human keratinocytes and human skin explants, we could show that UV radiation, applied either before or after contamination with PAH altered their metabolism and reduced both the production of metabolites and the formation of DNA damage. This work, carried out in collaboration with the Grenoble Hospital, was not limited to simple synthetic mixtures but also involved complex samples found at the work place. The effect of all the studied mixtures were modulated by sunlight.

Effect of simulated sunlight (SSL) on the induction of the gene coding for the metabolism enzyme CYP1A1 in human skin explants exposed to coal tar pitch (CTP). SSL was applied either before or after contamination. Results were obtained with skins form three different donors.