Skin permeation of nickel, cobalt and chromium salts in ex vivo human skin, visualized using mass spectrometry imaging

Hagvall, Lina; Pour, Masoumeh Dowlatshahi; Feng, Jiabao; Karma, Moshtak; Hedberg, Yolanda; Malmberg, Per

doi:10.1016/j.tiv.2021.105232

Cited by 18 publications

(23 citation statements)

References 29 publications

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“…Nickel deposition and stratum corneum penetration seems to be significant after relatively short exposure ( Ahlström et al, 2018 ). It is known that nickel is accumulated mostly in a bound state in stratum corneum ; in contrast, only minor concentrations were found below this layer in healthy skin ( Fullerton and Hoelgaard, 1988 ; Hagvall et al, 2021 ). Ahlström et al quantified metallic nickel penetration into the stratum corneum ; nickel deposition was found to be in the range between 10.1 and 23.5 μg/cm 2 after three 10-min exposures.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of nickel, there is certainly a strong possibility given the importance of FLG gene null mutations associated with nickel contact sensitization ( Novak et al, 2008 ; Thyssen et al, 2010 ). It is postulated that FLG chelate Ni 2+ ions by its numerous histidine side chains and prevent their penetration into deeper layers where interaction with the immune system can promote nickel sensitization ( Fullerton and Hoelgaard, 1988 ; Sigel et al, 1990 ; Thyssen et al, 2010 ; Hagvall et al, 2021 ). It should be first noted that the Ni 2+ -related FLG hydrolytic degradation yields specific oligopeptide complexes in which Ni 2+ ions are bound more strongly than the original substrate.…”

Section: Discussionmentioning

confidence: 99%

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Ni2+-Assisted Hydrolysis May Affect the Human Proteome; Filaggrin Degradation Ex Vivo as an Example of Possible Consequences

Podobas

Gutowska-Owsiak

Moretti

et al. 2022

Front. Mol. Biosci.

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Deficiency in a principal epidermal barrier protein, filaggrin (FLG), is associated with multiple allergic manifestations, including atopic dermatitis and contact allergy to nickel. Toxicity caused by dermal and respiratory exposures of the general population to nickel-containing objects and particles is a deleterious side effect of modern technologies. Its molecular mechanism may include the peptide bond hydrolysis in X1-S/T-c/p-H-c-X2 motifs by released Ni2+ ions. The goal of the study was to analyse the distribution of such cleavable motifs in the human proteome and examine FLG vulnerability of nickel hydrolysis. We performed a general bioinformatic study followed by biochemical and biological analysis of a single case, the FLG protein. FLG model peptides, the recombinant monomer domain human keratinocytes in vitro and human epidermis ex vivo were used. We also investigated if the products of filaggrin Ni2+-hydrolysis affect the activation profile of Langerhans cells. We found X1-S/T-c/p-H-c-X2 motifs in 40% of human proteins, with the highest abundance in those involved in the epidermal barrier function, including FLG. We confirmed the hydrolytic vulnerability and pH-dependent Ni2+-assisted cleavage of FLG-derived peptides and FLG monomer, using in vitro cell culture and ex-vivo epidermal sheets; the hydrolysis contributed to the pronounced reduction in FLG in all of the models studied. We also postulated that Ni-hydrolysis might dysregulate important immune responses. Ni2+-assisted cleavage of barrier proteins, including FLG, may contribute to clinical disease associated with nickel exposure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ni2+-Assisted Hydrolysis May Affect the Human Proteome; Filaggrin Degradation Ex Vivo as an Example of Possible Consequences

Podobas

Gutowska-Owsiak

Moretti

et al. 2022

Front. Mol. Biosci.

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“…Differences in the SC between control and nickel-treated samples were not observed ( Figure 4 ). Topically applied water-soluble nickel salts are deposited predominantly in the SC and only a small proportion passes into the VE, independent of the nickel salt used ( Hostýnek et al, 2001 ; Malmberg et al, 2018 ; Ahlström et al, 2019 ; Hagvall et al, 2021 ). The previously published findings from the nickel exposure of the skin tissue in the present study are in line with this ( Hagvall et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Unlike nickel, cobalt is known to penetrate through skin as it can be detected in urine samples after skin exposure ( Scansetti et al, 1994 ; Kettelarij et al, 2018 ). Within skin, cobalt distributes throughout the SC and VE after topical application in ex vivo human skin ( Hagvall et al, 2021 ). Cobalt skin exposure in occupational environments is unpredictable, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Previous methods have not been able to simultaneously detect both contact allergens and their effects on the skin tissue. We have presented a mass spectrometry imaging-based method able to detect both exogenous and endogenous compounds in skin tissue at the same time ( Malmberg et al, 2018 ; Hagvall et al, 2021 ). The method is an animal-free approach, as experiments can be performed ex vivo using human skin tissue which otherwise would be discarded.…”

Section: Introductionmentioning

confidence: 99%

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Topical Application of Metal Allergens Induces Changes to Lipid Composition of Human Skin

et al. 2022

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Lipids are an important constituent of skin and are known to be modified in many skin diseases including psoriasis and atopic dermatitis. The direct effects of common metallic contact allergens on the lipid composition of skin has never been investigated, to the best of our knowledge. We describe skin lipid profiles in the stratum corneum and viable epidermis of ex vivo human skin from a female donor upon exposure to three metal allergens (nickel, cobalt and chromium) visualised using time-of-flight secondary ion mass spectrometry (ToF-SIMS), which allows for simultaneous visualisation of both the allergen and skin components such as lipids. Multivariate analysis using partial least squares discriminant analysis (PLS-DA) indicated that the lipid profile of metal-treated skin was different to non-treated skin. Analysis of individual ions led to the discovery that cobalt and chromium induced increases in the content of diacylglycerols (DAG) in stratum corneum. Cobalt also induced increases in cholesterol in both the stratum corneum and viable epidermis, as well as monoacylglycerols (MAG) in the viable epidermis. Chromium caused an increase in DAG in viable epidermis in addition to the stratum corneum. In contrast, nickel decreased MAG and DAG levels in viable epidermis. Our results indicate that skin lipid content is likely to be altered upon topical exposure to metals. This discovery has potential implications for the molecular mechanisms by which contact allergens cause skin sensitization.

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Metabolipidomic changes induced by dermal nickel penetration determined in an ex vivo porcine ear skin model

Rezaei,

Ganashalingam,

Schindler

et al. 2024

Rapid Comm Mass Spectrometry

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RationalNickel is one of humans' most prevalent triggers of allergic contact dermatitis. However, the underlying mechanisms of this allergy still need to be fully understood. One aspect that has yet to be explored is the direct impact of common metal allergens on the skin's metabolites and lipids composition.MethodOur study employed matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to analyze spatially resolved metabolic alterations induced by nickel exposure. Cross‐sections of ex vivo porcine ear skin exposed to increasing nickel (II) ion concentrations (17–167 μg/cm2) were measured with an AP‐SMALDI5 AF ion source coupled to Q Exactive HF Orbitrap mass spectrometer. Additionally, the penetration of nickel ions into the skin was observed through its pink complexation with dimethylglyoxime under light microscopy.ResultsFor nickel ion concentrations up to 84 μg/cm2, most nickel ions were stopped within the stratum corneum, while only a very small proportion of nickel ions penetrated the viable epidermis and dermis. Stratum corneum locations with high nickel ion concentrations showed a decrease in arginine and ceramides. Furthermore, several phosphatidylcholine and sphingomyelin species were found to be downregulated in the viable epidermis and dermis due to the nickel exposure.ConclusionNickel penetrates at a trace level into the viable skin and induces severe metabolomic and lipidomic changes in the stratum corneum, epidermis, and dermis, indicating a change in the skin (barrier) function. These findings contribute to a deeper understanding of nickel‐induced skin allergies and provide a solid foundation for further research.

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Skin permeation of nickel, cobalt and chromium salts in ex vivo human skin, visualized using mass spectrometry imaging

Cited by 18 publications

References 29 publications

Ni2+-Assisted Hydrolysis May Affect the Human Proteome; Filaggrin Degradation Ex Vivo as an Example of Possible Consequences

Ni2+-Assisted Hydrolysis May Affect the Human Proteome; Filaggrin Degradation Ex Vivo as an Example of Possible Consequences

Topical Application of Metal Allergens Induces Changes to Lipid Composition of Human Skin

Metabolipidomic changes induced by dermal nickel penetration determined in an ex vivo porcine ear skin model

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