Raffalli C, Clouet E, Kuresepi S, Damiens MH, Lepoittevin JP, Pallardy M, Ferret PJ, Giménez-Arnau E, Kerdine-Römer S
Toxicology Science, 2017
Allergic contact dermatitis (ACD) is regarded as the most frequent expression of immunotoxicity in humans. Many odorant terpenes commonly used in fragrance compositions are considered as weak skin sensitizers, whereas some of their autoxidation products, allylic hydroperoxides, are classified as strong sensitizers according to the Local Lymph Node Assay (LLNA). However, the mechanism of their effects on the immune system remains unclear. Since dendritic cells play a key role in ACD, we studied their activation by the frequently used linalool(LINA) and limonene (LIMO), and their respective sensitizing allylic hydroperoxides (LINA-OOH, LIMO-OOH). The THP-1 cell line was used as a surrogate for dendritic cells, the model currently employed in the validated h-CLAT in vitro test.Our data showed that allylic hydroperoxides behave differently. Both LINA-OOH and LIMO-OOH, oxidized cell surface thiols 30 min after stimulation. However, the oxidative stress induced by LINA-OOH was stronger, with a higher decreased GSH/GSSG ratio and a stronger reactive species production. Moreover, LINA-OOH induced a stronger Nrf2 accumulation in correlation with nqo1 and ho-1 gene expression, two Nrf2 target genes. Regarding signaling pathways involved in these effects, P38 MAPK and P-ERK were activated in response to LINA-OOH but not with LIMO-OOH. CD54 and CD86 were induced 24 h post exposure. In contrast LINA and LIMO did not modify THP-1 phenotype.This work underlies that autoxidation forming allylic hydroperoxide (ROOH) does not lead to equal chemical reactivity since LINA-OOH appears to be a stronger activator than LIMO-OOH, in regard to oxidative stress and Nrf2 pathway activation.
Raffalli C, Clouet E, Kuresepi S et al. Fragrance allergens linalool and limonene allylic hydroperoxides in skin allergy: mechanisms of action focusing on transcription factor Nrf2. Toxicol Sci. 2017 Sep 29. doi: 10.1093/toxsci/kfx207.