Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Adjuvants in fungicide formulations can be skin sensitizers and cause different types of cell stress responses

de Ávila, Renato Ivan LU ; Carreira Santos, Sofía LU ; Siino, Valentina LU ; Levander, Fredrik LU ; Lindstedt, Malin LU and Zeller, Kathrin S. LU orcid (2022) In Toxicology Reports 9. p.2030-2041
Abstract

New approaches based on -omics technologies can identify biomarkers and processes regulated in response to xenobiotics, and thus support toxicological risk assessments. This is vital to meet the challenges associated with “cocktail effects”, i.e. combination effects of chemicals present simultaneously in a product, our environment, and/or our body. For plant protection products (PPPs), investigations largely focus on active ingredients such as herbicides and fungicides. In this study, we have analyzed agricultural chemicals, two surfactants (poly(oxy-1,2-ethanediyl), alpha-sulfo-omega-[2,4,6-tris(1-phenylethyl)phenoxy]-, ammonium salt, POL; N,N-dimethylcapramide, NND), and one preservative, 1,2-benzisothiazol-3(2 H)-one (BEN) used as... (More)

New approaches based on -omics technologies can identify biomarkers and processes regulated in response to xenobiotics, and thus support toxicological risk assessments. This is vital to meet the challenges associated with “cocktail effects”, i.e. combination effects of chemicals present simultaneously in a product, our environment, and/or our body. For plant protection products (PPPs), investigations largely focus on active ingredients such as herbicides and fungicides. In this study, we have analyzed agricultural chemicals, two surfactants (poly(oxy-1,2-ethanediyl), alpha-sulfo-omega-[2,4,6-tris(1-phenylethyl)phenoxy]-, ammonium salt, POL; N,N-dimethylcapramide, NND), and one preservative, 1,2-benzisothiazol-3(2 H)-one (BEN) used as adjuvants in PPPs, and further three fungicide PPPs, Proline EC 250, Shirlan, Folicur Xpert, containing the adjuvants, and other major individual constituents (fluazinam (FLU), prothioconazole (PRO), tebuconazole (TEB)) as well as defined mixtures (“mixes”) thereof using several in vitro approaches. All investigated single agricultural chemicals were predicted as skin sensitizers using an in vitro transcriptomic assay based on a dendritic cell model. For selected chemicals and mixes, also skin sensitization potency was predicted. The preservative BEN induced significant changes in cytokine secretion and dendritic cell activation marker CD86 expression. The surfactant NND changed cytokine secretion only and the POL only affected CD86 expression. Proteomic analyses revealed unique response profiles for all adjuvants, an oxidative stress pattern response in BEN-treated cells, and differentially abundant proteins associated with cholesterol homeostasis in response to POL. In summary, we find responses to agricultural chemicals and products consistent with the dendritic cell model reacting to chemical exposure with oxidative stress, ER stress, effects on autophagy, and metabolic changes especially related to cholesterol homeostasis. After exposure to certain mixes, novel proteins or transcripts were differentially expressed and these were not detected for any single constituents, supporting the occurrence of cocktail effects. This indicates that all chemicals in a PPP can contribute to the toxicity profile of a PPP, including their skin sensitizing/immunotoxic properties.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cocktail effects, Immunotoxicity, in vitro models, Omics approaches, Plant protection products, Skin sensitization
in
Toxicology Reports
volume
9
pages
12 pages
publisher
Elsevier
external identifiers
  • pmid:36518395
  • scopus:85142501185
ISSN
2214-7500
DOI
10.1016/j.toxrep.2022.11.004
language
English
LU publication?
yes
additional info
Funding Information: This study has been supported by the Crafoord Foundation [ 20190834 ], the Research Council Formas [ 2017–01030, 2019–01093 ], Stiftelsen Sigurd och Elsa Goljes Minne [ LA2020–0103 ]. We thank Senzagen AB for support to run assays based on GARD® assays. We also thank Linda Ljungberg Silic (Lund Univ.) for technical assistance. Funding Information: This study has been supported by the Crafoord Foundation [20190834], the Research Council Formas [2017–01030, 2019–01093], Stiftelsen Sigurd och Elsa Goljes Minne [LA2020–0103]. We thank Senzagen AB for support to run assays based on GARD® assays. We also thank Linda Ljungberg Silic (Lund Univ.) for technical assistance. Publisher Copyright: © 2022 The Authors
id
9afed5f4-0964-4722-93b9-7877fd56059c
date added to LUP
2022-12-20 09:26:35
date last changed
2024-06-13 21:54:35
@article{9afed5f4-0964-4722-93b9-7877fd56059c,
  abstract     = {{<p>New approaches based on -omics technologies can identify biomarkers and processes regulated in response to xenobiotics, and thus support toxicological risk assessments. This is vital to meet the challenges associated with “cocktail effects”, i.e. combination effects of chemicals present simultaneously in a product, our environment, and/or our body. For plant protection products (PPPs), investigations largely focus on active ingredients such as herbicides and fungicides. In this study, we have analyzed agricultural chemicals, two surfactants (poly(oxy-1,2-ethanediyl), alpha-sulfo-omega-[2,4,6-tris(1-phenylethyl)phenoxy]-, ammonium salt, POL; N,N-dimethylcapramide, NND), and one preservative, 1,2-benzisothiazol-3(2 H)-one (BEN) used as adjuvants in PPPs, and further three fungicide PPPs, Proline EC 250, Shirlan, Folicur Xpert, containing the adjuvants, and other major individual constituents (fluazinam (FLU), prothioconazole (PRO), tebuconazole (TEB)) as well as defined mixtures (“mixes”) thereof using several in vitro approaches. All investigated single agricultural chemicals were predicted as skin sensitizers using an in vitro transcriptomic assay based on a dendritic cell model. For selected chemicals and mixes, also skin sensitization potency was predicted. The preservative BEN induced significant changes in cytokine secretion and dendritic cell activation marker CD86 expression. The surfactant NND changed cytokine secretion only and the POL only affected CD86 expression. Proteomic analyses revealed unique response profiles for all adjuvants, an oxidative stress pattern response in BEN-treated cells, and differentially abundant proteins associated with cholesterol homeostasis in response to POL. In summary, we find responses to agricultural chemicals and products consistent with the dendritic cell model reacting to chemical exposure with oxidative stress, ER stress, effects on autophagy, and metabolic changes especially related to cholesterol homeostasis. After exposure to certain mixes, novel proteins or transcripts were differentially expressed and these were not detected for any single constituents, supporting the occurrence of cocktail effects. This indicates that all chemicals in a PPP can contribute to the toxicity profile of a PPP, including their skin sensitizing/immunotoxic properties.</p>}},
  author       = {{de Ávila, Renato Ivan and Carreira Santos, Sofía and Siino, Valentina and Levander, Fredrik and Lindstedt, Malin and Zeller, Kathrin S.}},
  issn         = {{2214-7500}},
  keywords     = {{Cocktail effects; Immunotoxicity; in vitro models; Omics approaches; Plant protection products; Skin sensitization}},
  language     = {{eng}},
  pages        = {{2030--2041}},
  publisher    = {{Elsevier}},
  series       = {{Toxicology Reports}},
  title        = {{Adjuvants in fungicide formulations can be skin sensitizers and cause different types of cell stress responses}},
  url          = {{http://dx.doi.org/10.1016/j.toxrep.2022.11.004}},
  doi          = {{10.1016/j.toxrep.2022.11.004}},
  volume       = {{9}},
  year         = {{2022}},
}