Novel Photoinduced Squalene Cyclic Peroxide Identified, Detected, and Quantified in Human Skin Surface Lipids.

Saoussane Khalifa,Shunji Kato,Kiyotaka Nakagawa,Masaru Enomoto

doi:10.3390/antiox10111760

Abstract

Skin surface lipids (SSLs) form the first barrier that protects the human organism from external stressors, disruption of the homeostasis of SSLs can result in severe skin abnormalities. One of the main causes of this disruption is oxidative stress that is primarily due to SSLs oxidation. Squalene (SQ), the most abundant lipid among SSLs, was shown to first undergo singlet molecular oxygen (1O2) oxidation to yield 6 SQ-monohydroperoxide (SQ-OOH) isomers as the primary oxidation products. However, due to the instability and lability of hydroperoxides, we found that when total SQ-OOH isomers are further photooxidized, they form a unique higher molecular weight secondary oxidation product. To generate the compound, we photooxidized total SQ-OOH isomers in the presence of ground state molecular oxygen (3O2), after its isolation and purification, we studied its structure using MS/MS, NMR, derivatization reactions, and chemical calculations. The compound was identified as 2-OOH-3-(1,2-dioxane)-SQ. Photooxidation of individual SQ-OOH isomers revealed that 6-OOH-SQ is the precursor of 2-OOH-3-(1,2-dioxane)-SQ and indicated the possibility of the formation of similar cyclic peroxides from each isomer following the same photoinduced chain reaction mechanism. An HPLC-MS/MS method was developed for the analysis of 2-OOH-3-(1,2-dioxane)-SQ and its presence on the skin was confirmed in SSLs of six healthy individuals. Its quantity on the skin correlated directly to that of SQ and was not inversely proportional to its precursor, indicating the possibility of its accumulation on the skin surface and the constant regeneration of 6-OOH-SQ from SQ’s oxidation. In general, research on lipid cyclic peroxides in the human organism is very limited, and especially on the skin. This study shows for the first time the identification and presence of a novel SQ cyclic peroxide “2-OOH-3-(1,2-dioxane)-SQ” in SSLs, shedding light on the importance of further studying its effect and role on the skin.

Highlights

The skin forms the first defense line that protects the organism against external stressors and pathogens due to its hydrophobic coating with skin surface lipids (SSLs) [1].Dysregulation of SSLs’ function has been linked to their oxidation resulting in serious skin conditions such as premature aging, melanoma, inflammatory and allergic diseases [2,3,4].For instance, malondialdehyde (MDA) has been shown to be involved in cell ferroptosis induced in melanoma [5]
SQ-OOH, various lipid hydroperoxides, as well as certain lipid breakdown products such as MDA, have been often used as oxidative stress biomarkers [55], we demonstrated in this study the lability and instability of SQ-OOH isomers in conditions to which the skin is often exposed, we suggest that 2-OOH-3-(1,2-dioxane)-SQ can be used as a more stable biomarker to better demonstrate the level of oxidative stress on the skin
We identified a novel SQ secondary oxidation product as 2-OOH-3In this study, we identified novel

Summary

Introduction

The skin forms the first defense line that protects the organism against external stressors and pathogens due to its hydrophobic coating with skin surface lipids (SSLs) [1]. Malondialdehyde (MDA) has been shown to be involved in cell ferroptosis induced in melanoma [5]. Squalene (SQ) (SQ, Figure 1), the most abundant among SSLs (12%), and a precursor of natural steroids [7,8,9], plays an overall protective role on the skin, as it acts as an antioxidant and a protective barrier [10,11], it enhances the skin’s immunity through the promotion of IL-1β and the activation of T cells [12,13].

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