Thyroid tumor formation in the male mouse induced by fluopyram is mediated by activation of hepatic CAR/PXR nuclear receptors

Rouquié, David; Tinwell, H.; Blanck, Olivier; Schorsch, Frédéric; Geter, David R.; Wason, Sheila; Bars, R.

doi:10.1016/j.yrtph.2014.10.003

Cited by 35 publications

(24 citation statements)

References 28 publications

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“…In spite of the compensation of yield loss, food safety issues and ecological risks conversely caused by the excessive application of fungicides in vegetables have been raised as public concerns recently worldwide 2 8 . Fluopyram was classified as a low toxic compound due to the relatively low LD 50 towards mammals (for rats, >2000 mg/kg bw), but it was also known to act as an endocrine disrupting compound (EDC) to exert side effects on the endocrine systems of human beings and wildlife at trace level 9 10 11 . For instance, it could induce tumor formation in the liver and thyroid of the rat by activation of CAR/PXR nuclear receptor 10 12 .…”

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confidence: 99%

“…Fluopyram was classified as a low toxic compound due to the relatively low LD 50 towards mammals (for rats, >2000 mg/kg bw), but it was also known to act as an endocrine disrupting compound (EDC) to exert side effects on the endocrine systems of human beings and wildlife at trace level 9 10 11 . For instance, it could induce tumor formation in the liver and thyroid of the rat by activation of CAR/PXR nuclear receptor 10 12 . More recently, it was also found that this fungicide was capable of altering the microbial diversity in soil ecosystem, leading to depraved soil health 13 .…”

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confidence: 99%

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Metabolic and Dynamic Profiling for Risk Assessment of Fluopyram, a Typical Phenylamide Fungicide Widely Applied in Vegetable Ecosystem

Peng

Liu

et al. 2016

Sci Rep

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Fluopyram, a typical phenylamide fungicide, was widely applied to protect fruit vegetables from fungal pathogens-responsible yield loss. Highly linked to the ecological and dietary risks, its residual and metabolic profiles in the fruit vegetable ecosystem still remained obscure. Here, an approach using modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) extraction combined with GC-MS/MS analysis was developed to investigate fluopyram fate in the typical fruit vegetables including tomato, cucumber, pepper under the greenhouse environment. Fluopyram dissipated in accordance with the first-order rate dynamics equation with the maximum half-life of 5.7 d. Cleveage of fluopyram into 2-trifluoromethyl benzamide and subsequent formation of 3-chloro-5-(trifluoromethyl) pyridine-2-acetic acid and 3-chloro-5-(trifluoromethyl) picolinic acid was elucidated to be its ubiquitous metabolic pathway. Moreover, the incurrence of fluopyram at the pre-harvest interval (PHI) of 7–21 d was between 0.0108 and 0.1603 mg/kg, and the Hazard Quotients (HQs) were calculated to be less than 1, indicating temporary safety on consumption of the fruit vegetables incurred with fluopyram, irrespective of the uncertain toxicity of the metabolites. Taken together, our findings reveal the residual essential of fluopyram in the typical agricultural ecosystem, and would advance the further insight into ecological risk posed by this fungicide associated with its metabolites.

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confidence: 99%

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confidence: 99%

Metabolic and Dynamic Profiling for Risk Assessment of Fluopyram, a Typical Phenylamide Fungicide Widely Applied in Vegetable Ecosystem

Peng

Liu

et al. 2016

Sci Rep

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“…However, PXR activation also induces differentiation of osteoblasts and apoptosis of osteoclasts and certain leukemia cells (Austin et al, 2015; Hassen et al, 2014; Igarashi et al, 2007; Kameda et al, 1996; Tabb et al, 2003), suggesting that control of cell proliferation by PXR is likely tissue and cell-specific. A similar theme plays out in cancer cells, in which, PXR differentially regulates cell growth through multiple mechanisms in a variety of cancers, including liver, prostate, breast, ovarian, endometrial, cervical, and colon (Braeuning et al, 2014; Kakehashi et al, 2013; Koutsounas et al, 2013; Luisier et al, 2014; Ma et al, 2015; Niu et al, 2014; Pondugula and Mani, 2013; Qiao et al, 2013; Ross et al, 2010; Rouquie et al, 2014; Shizu et al, 2013; Tinwell et al, 2014). Additionally, PXR is involved in regulating metastasis of cancer cells (Gupta et al, 2008; Masuyama et al, 2007; Wang et al, 2011).…”

Section: Introductionmentioning

confidence: 85%

Pregnane X Receptor and Cancer: Context-Specificity is Key

Pondugula

Pávek

Mani

2016

Nuclear Receptor Research

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Pregnane X receptor (PXR) is an adopted orphan nuclear receptor that is activated by a wide-range of endobiotics and xenobiotics, including chemotherapy drugs. PXR plays a major role in the metabolism and clearance of xenobiotics and endobiotics in liver and intestine via induction of drug-metabolizing enzymes and drug-transporting proteins. However, PXR is expressed in several cancer tissues and the accumulating evidence strongly points to the differential role of PXR in cancer growth and progression as well as in chemotherapy outcome. In cancer cells, besides regulating the gene expression of enzymes and proteins involved in drug metabolism and transport, PXR also regulates other genes involved in proliferation, metastasis, apoptosis, anti-apoptosis, inflammation, and oxidative stress. In this review, we focus on the differential role of PXR in a variety of cancers, including prostate, breast, ovarian, endometrial, and colon. We also discuss the future directions to further understand the differential role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators to target PXR in PXR-expressing cancers.

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“…However, the oral rat LD 50 of fluopyram was >2000 mg kg -1 (European Food Safety Authority 2011), which was much higher than the prediction value. In addition, fluopyram caused thyroid tumors and liver tumors (Rouquié et al 2014;Tinwell et al 2014). Therefore, in vivo and in vitro assays should be fulfilled in order to assess the toxicity of these compounds.…”

Section: Sift Deskmentioning

confidence: 99%

“…Fluopyram is non-toxic to mammals, birds, honeybees and duck, slightly toxic to daphnia and freshwater green algae, and moderately toxic, even highly toxic to freshwater fish and marine species (The Health Canada Pest Management Regulatory Agency 2014). Fluopyram is an endocrine disrupting compound on the endocrine systems of human beings and wildlife at trace level (Rouquié et al 2014;Tinwell et al 2014). In addition, it has a negative effect on overall soil microbial activity and changes soil microbial community structure and function (Zhang et al 2014).…”

Section: Introduction Fluopyrammentioning

confidence: 99%

Mechanism and identify photolysis products of fluopyram under TiO2: Experiments, DFT and ab initio Molecular dynamics study

Pang¹,

Dong²,

Desk³

2019

SDRP-JESES

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Fluopyram is one of the widely used fungicides and it is persistence in water and soil. In this study, the photocatalytic degradation of fluopyram by TiO 2 was investigated under simulated solar light irradiation. Six transformation products (TPs) were identified by means of high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) and the quantum chemistry calculations (DFT and AIMD method). The formation of these TPs involved the hydroxyl-substitution of Cl atom, intramolecular cyclization, cleavage of amido bond, loss of trifluorotoluene, and attack of hydroxyl group on benzene ring. And then, a tentative pathway of the photocatalytic degradation was proposed. The toxicity of fluopyram and its TPs were predicted using in silico test. The results showed that potentially more toxic intermediates formed during photocatalytic degradation. These data suggested that more information about TPs of fluopyram and their toxicity should be obtained.

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Thyroid tumor formation in the male mouse induced by fluopyram is mediated by activation of hepatic CAR/PXR nuclear receptors

Cited by 35 publications

References 28 publications

Metabolic and Dynamic Profiling for Risk Assessment of Fluopyram, a Typical Phenylamide Fungicide Widely Applied in Vegetable Ecosystem

Metabolic and Dynamic Profiling for Risk Assessment of Fluopyram, a Typical Phenylamide Fungicide Widely Applied in Vegetable Ecosystem

Pregnane X Receptor and Cancer: Context-Specificity is Key

Mechanism and identify photolysis products of fluopyram under TiO2: Experiments, DFT and ab initio Molecular dynamics study

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