An integrated in silico-in vitro investigation to assess the skin sensitization potential of 4-Octylphenol

Souza, Isisdoris Rodrigues de; Iulini, Martina; Galbiati, Valentina; Silva, Enzo Zini Moreira; Sivek, Tainá Wilke; Rodrigues, Ana Carolina; Gradia, Daniela Fiori; Pestana, C B; Leme, Daniela Morais; Corsini, Emanuela

doi:10.1016/j.tox.2023.153548

Cited by 2 publications

(4 citation statements)

References 69 publications

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“…NAMs, and combinations of the so-called defined approaches reflecting the first three of the four KEs within the skin sensitization AOP, are coming to displace the corresponding in vivo tests—with their predictivity demonstrated to be acceptable (de Souza et al 2023 ; Caloni et al 2022 ; Wei et al 2024 ). However, these predictions are mainly based on the testing of simple substances.…”

Section: Discussionmentioning

confidence: 99%

“…MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and NEAT1 (nuclear-enriched abundant transcript 1) often form relatively stable secondary and higher structures, may regulate various cell signaling molecules (Tang et al 2020 ) and have been associated with psoriasis, for instance (Zhang et al 2021 ). A recent study from our group demonstrated that the MALAT1 and NEAT1 genes can have their expression affected by the conventional chemical substance Octylphenol (de Souza et al 2023 ). However, unlike in the study of Octylphenol, DiPeP did not change the expression of these lncRNA genes by either downregulation or upregulation of their expression.…”

Section: Discussionmentioning

confidence: 99%

“…Chemicals with the potential to present immunomodulatory effects can enhance inflammatory reactions on the skin, affect the development of allergy and, consequently, affect human health in ways not anticipated in the assessment of the chemical individually (Corsini et al 2011 , 2012 ; de Souza et al 2023 ; Wong Lau et al 2023 ). Along these lines, LPS-induced THP-1 activation assay has been proposed to address immunomodulatory effects of chemicals and it is based on the observation of an increase or a decrease in the response of cells to LPS, after exposure to the tested substances, indicating enhancement or suppression of immune response (DC activation) to an inflammatory agent (Bosshart and Heinzelmann 2016 ; Galbiati et al 2010 ; Masi et al 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…84777-06-0 is described as a UVCB, the effects and limitations of using new approach methodologies (NAMs) in characterizing the hazard potential of this latter “difficult-to-test substance” were evaluated using an assortment of complementary in silico and in vitro methods (both OECD-approved and non-conventional). The same set of approaches was successfully applied in a previous study relating to 4-Octylphenol (OP), an environmental contaminant with widespread distribution (de Souza et al 2023 ).…”

Section: Introductionmentioning

confidence: 99%

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The evaluation of skin sensitization potential of the UVCB substance diisopentyl phthalate by in silico and in vitro methods

de Souza,

Iulini,

Galbiati

et al. 2024

Arch Toxicol

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Diisopentyl phthalate (DiPeP) is primarily used as a plasticizer or additive within the production of polyvinyl chloride (PVC), and has many additional industrial applications. Its metabolites were recently found in urinary samples of pregnant women; thus, this substance is of concern as relates to human exposure. Depending upon the nature of the alcohol used in its synthesis, DiPeP may exist either as a mixture consisting of several branched positional isomers, or as a single defined structure. This article investigates the skin sensitization potential and immunomodulatory effects of DiPeP CAS No. 84777-06-0, which is currently marketed and classified as a UVCB substance, by in silico and in vitro methods. Our findings showed an immunomodulatory effect for DiPeP in LPS-induced THP-1 activation assay (increased CD54 expression). In silico predictions using QSAR TOOLBOX 4.5, ToxTree, and VEGA did not identify DiPeP, in the form of a discrete compound, as a skin sensitizer. The keratinocyte activation (Key Event 2 (KE2) of the adverse outcome pathway (AOP) for skin sensitization) was evaluated by two different test methods (HaCaT assay and RHE assay), and results were discordant. While the HaCaT assay showed that DiPeP can activate keratinocytes (increased levels of IL-6, IL-8, IL-1α, and ILA gene expression), in the RHE assay, DiPeP slightly increased IL-6 release. Although inconclusive for KE2, the role of DiPeP in KE3 (dendritic cell activation) was demonstrated by the increased levels of CD54 and IL-8 and TNF-α in THP-1 cells (THP-1 activation assay). Altogether, findings were inconclusive regarding the skin sensitization potential of the UVCB DiPeP—disagreeing with the results of DiPeP in the form of discrete compound (skin sensitizer by the LLNA assay). Additional studies are needed to elucidate the differences between DiPeP isomer forms, and to better understand the applicability domains of non-animal methods in identifying skin sensitization hazards of UVCB substances.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The evaluation of skin sensitization potential of the UVCB substance diisopentyl phthalate by in silico and in vitro methods

de Souza,

Iulini,

Galbiati

et al. 2024

Arch Toxicol

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In Vitro Investigation of Biological and Toxic Effects of 4-Octylphenol on Human Cells

Romanelli,

Montefusco,

Sposito

et al. 2024

IJMS

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Alkylphenols are byproducts of anthropogenic activities that widely contaminate waters, soils and air; among them, the most represented are 4-nonylphenol (4-NP) and 4-octylphenol (4-OP). These compounds tend to bioaccumulate in animal and plant tissues and also represent a risk to human health. Indeed, humans are constantly exposed to alkylphenols through ingestion of contaminated water and food, inhalation and dermal absorption. In the present work, we characterized the cytotoxic ability of 4-OP towards several human cell lines, representing the potential main targets in the human body, also comparing its effect with that of 4-NP and of a mixture of both 4-OP and 4-NP in a range of concentrations between 1 and 100 μM. Viability assays demonstrated that each cell type had a peculiar sensitivity to 4-OP and that, in some cases, a combination of the two alkylphenols displayed a higher cytotoxic activity with respect to the single compound. Then, we focused our attention on a liver cell line (HepG2) in which we observed that 4-OP increased cell death and also caused interference with protective physiological cell processes, such as the unfolded protein response, autophagy and the antioxidant response. Finally, our experimental data were compared and correlated with ADMET properties originating from an in silico analysis. Altogether, our findings highlight a possible contribution of this pollutant to deregulation of the normal homeostasis in human liver cells.

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An integrated in silico-in vitro investigation to assess the skin sensitization potential of 4-Octylphenol

Cited by 2 publications

References 69 publications

The evaluation of skin sensitization potential of the UVCB substance diisopentyl phthalate by in silico and in vitro methods

The evaluation of skin sensitization potential of the UVCB substance diisopentyl phthalate by in silico and in vitro methods

In Vitro Investigation of Biological and Toxic Effects of 4-Octylphenol on Human Cells

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