An adverse outcome pathway-based approach to assess steatotic mixture effects of hepatotoxic pesticides in vitro

Lichtenstein, Dajana; Luckert, Claudia; Alarcan, Jimmy; Sousa, Georges de; Gioutlakis, Michail; Katsanou, Efrosini S.; Konstantinidou, Parthena; Machera, Kyriaki; Milani, Emanuela S.; Peijnenburg, Ad; Rahmani, Roger; Rijkers, Deborah; Spyropoulou, Anastasia; Stamou, Marianna; Stoopen, Geert; Sturla, Shana J.; Wollscheid, Bernd; Zucchini-Pascal, Nathalie; Braeuning, Albert; Lampen, Alfonso

doi:10.1016/j.fct.2020.111283

Cited by 53 publications

(68 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, in this study, THI was found to activate PXR and peroxisome proliferator-activated receptor γ (PPARγ) while CTD inhibited PPARα. These findings on PXR and CAR activation were complemented by the observation of up-regulation in the expression of associated target genes (e.g., CYP genes) in human HepaRG hepatocarcinoma cells (Lichtenstein et al 2020). Of note, an increase in CYP content in rats following 30-day treatment with THI was also reported by others (Hendawi et al 2016).…”

Section: Introductionsupporting

confidence: 60%

“…Even after having documented the toxicological effects at the histopathological level, the mechanisms by which IMZ, THI and CTD induce adverse effects at the molecular level are still to be characterized. Using transfected human HepG2 liver cells, we previously showed the activation of human pregnane X receptor (PXR) and constitutive androstane receptor (CAR) by IMZ in a dual luciferase-based transactivation assay (Lichtenstein et al 2020). Furthermore, in this study, THI was found to activate PXR and peroxisome proliferator-activated receptor γ (PPARγ) while CTD inhibited PPARα.…”

Section: Introductionmentioning

confidence: 69%

“…This is in line with the observation of liver hypertrophy following exposure to IMZ, THI and CTD, as the nuclear receptor-mediated induction of metabolic enzymes causes an increase in endoplasmic reticulum, peroxisomes and/or mitochondria. Previous studies showed that IMZ activates both human and mouse PXR and also human CAR (Lichtenstein et al 2020;Yoshimaru et al 2018). Besides, THI activated human PXR and PPARγ while CTD showed no effect on human PXR or CAR (Lichtenstein et al 2020).…”

Section: Discussionmentioning

confidence: 92%

See 2 more Smart Citations

Transcriptomics analysis of hepatotoxicity induced by the pesticides imazalil, thiacloprid and clothianidin alone or in binary mixtures in a 28-day study in female Wistar rats

et al. 2021

Self Cite

View full text Add to dashboard Cite

Co-occurrence of pesticide residues in food commodities raises a potential safety issue as their mixture effects on human health are largely unknown. In a previous study, we reported the toxicological effects (pathology and histopathology) of imazalil (IMZ), thiacloprid (THI), and clothianidin (CTD) alone and in binary mixtures in a 28-day oral gavage study in female Wistar rats. Five dose levels (up to 350 mg/kg body weight/day) ranging from a typical toxicological reference value to a clear effect dose were applied. In the present study, we undertook a transcriptomics analysis of rat livers by means of total RNA sequencing (RNA-Seq). Bioinformatic data analysis involving Ingenuity Pathway Analysis (IPA) was used to gain mechanistic information on hepatotoxicity-related pathways affected after treatment with the pesticides, alone and in mixtures. Our data show that 2986 genes were differentially regulated by CTD while IMZ and THI had effects on 194 and 225 genes, respectively. All three individual compounds shared a common subset of genes whose network is associated with xenobiotic metabolism and nuclear receptor activation. Similar networks were retrieved for the mixtures. Alterations in the expression of individual genes were in line with the assumption of dose addition. Our results bring new insight into the hepatotoxicity mechanisms of IMZ, THI, and CTD and their mixtures.

show abstract

Section: Introductionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

Transcriptomics analysis of hepatotoxicity induced by the pesticides imazalil, thiacloprid and clothianidin alone or in binary mixtures in a 28-day study in female Wistar rats

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Because the liver is one of the most prominent target organs and may be investigated using the human liver cell-derived HepaRG™ assay, it was also proposed as part of the EuroMix test battery. 71 The HepaRG™ model has also been implemented in a draft OECD test guideline required for regulatory acceptance. 72 To evaluate sub-chronic toxicity, we furthermore suggest the zebrafish embryo toxicity assay, which has been validated and is regulatory accepted for developmental endpoints.…”

Section: Tiered Toxicity Testingmentioning

confidence: 99%

Towards a tiered test strategy for plant protection products to address mixture toxicity by alternative approaches in human health assessment

Bloch

Marx‐Stoelting

Martin

2020

Pest Management Science

View full text Add to dashboard Cite

Plant protection products (PPPs) consist of pesticide active substances and co‐formulants. Generally, active substance effects are assumed to dominate in PPP toxicity. Nevertheless, co‐formulants may well affect the toxicity of PPPs via toxicodynamic and toxicokinetic interaction. To account for potential mixture effects and improve PPP data requirements for application in risk assessment, a tiered test strategy is proposed. The strategy is based on a comparison of PPP and active substance toxicity, which enables the prioritisation of PPPs for further testing, adaptation of the toxicological threshold value or removal of toxic co‐formulants from the PPP. Moreover, it focuses on the integrative assessment of existing information and newly generated data using alternative test methods. The proposed strategy will improve PPP toxicological assessment by accounting for mixture toxicity, providing a set of regulatory options for risk assessment and the necessary data for hazard assessment. The predictivity of alternative methods for PPPs will improve by evaluation of their reliability and uncertainty. © 2020 The Authors. Pest Management Science published by JohnWiley & Sons Ltd on behalf of Society of Chemical Industry.

show abstract

“…More recent examples of newly developed tools to predict effects of mixtures can be found in the Horizon 20/20 EuroMix projects (Bopp et al 2018;Lichtenstein et al 2020;Rotter et al 2018). Three different end points were selected for case study development: liver steatosis, adverse reproductive effects from endocrine disruption, and craniofacial malformations (Rotter et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Using the Key Characteristics of Carcinogens to Develop Research on Chemical Mixtures and Cancer

Rider

McHale

Webster

et al. 2021

Environ Health Perspect

View full text Add to dashboard Cite

BACKGROUND: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit. Challenges involved in designing research studies to evaluate the joint action of chemicals on cancer risk include the time taken to perform the experiments because of the long latency and choosing an appropriate experimental design. OBJECTIVES: The objectives of this work are to present the case for developing a research program on mixtures of environmental chemicals and cancer risk and describe recommended approaches. METHODS: A working group comprising the coauthors focused attention on the design of mixtures studies to inform cancer risk assessment as part of a larger effort to refine the key characteristics of carcinogens and explore their application. Working group members reviewed the key characteristics of carcinogens, hallmarks of cancer, and mixtures research for other disease end points. The group discussed options for developing tractable projects to evaluate the joint effects of environmental chemicals on cancer development. RESULTS AND DISCUSSION: Three approaches for developing a research program to evaluate the effects of mixtures on cancer development were proposed: a chemical screening approach, a transgenic model-based approach, and a disease-centered approach. Advantages and disadvantages of each are discussed.

show abstract

An adverse outcome pathway-based approach to assess steatotic mixture effects of hepatotoxic pesticides in vitro

Cited by 53 publications

References 52 publications

Transcriptomics analysis of hepatotoxicity induced by the pesticides imazalil, thiacloprid and clothianidin alone or in binary mixtures in a 28-day study in female Wistar rats

Transcriptomics analysis of hepatotoxicity induced by the pesticides imazalil, thiacloprid and clothianidin alone or in binary mixtures in a 28-day study in female Wistar rats

Towards a tiered test strategy for plant protection products to address mixture toxicity by alternative approaches in human health assessment

Using the Key Characteristics of Carcinogens to Develop Research on Chemical Mixtures and Cancer

Contact Info

Product

Resources

About