Concentration-dependent effects of chlorpyrifos oxon on peroxisome proliferator-activated receptor signaling in MCF-7 cells

Herriage, Stacey; Chen, Guangping; Pope, Carey

doi:10.1016/j.tiv.2021.105268

Cited by 12 publications

(5 citation statements)

References 78 publications

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“…Again, changes in brain CYP2B6 expression may lead to increased metabolism and impaired duration of action of bupropion, thereby affecting outcomes of smoking cessation treatment ( Lee et al, 2007 ). Upregulation of CYP2B6 can also increase the toxicological risk associated with the environmental exposure of some pesticides such as chlorpyrifos, which is converted to the neurotoxic oxon metabolite mainly by CYP2B6 ( Herriage et al, 2022 ). Interestingly, increased CYP2E1 expression was observed in the PFC of alcoholics and smokers and was associated with ethanol and nicotine dependence ( García-Suástegui et al, 2017 ); in addition, evidence from animal models indicates that CYP2E1 induction exacerbates neurological deficit and increases oxidative stress, inflammation, and neurodegeneration ( Yu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of unburned tobacco smoke on inflammatory and oxidative mediators in the rat prefrontal cortex

Vivarelli,

Morosini,

Rullo

et al. 2024

Front. Pharmacol.

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Although the Food and Drug Administration has authorized the marketing of “heat-not-burn” (HnB) electronic cigarettes as a modified risk tobacco product (MRTP), toxicological effects of HnB smoke exposure on the brain are still unexplored. Here, paramagnetic resonance of the prefrontal cortex (PFC) of HnB-exposed rats shows a dramatic increase in reactive radical species (RRS) yield coupled with an inflammatory response mediated by NF-κB-target genes including TNF-α, IL-1β, and IL-6 and the downregulation of peroxisome proliferator-activated receptor (PPAR) alpha and gamma expression. The PFC shows higher levels of 8-hydroxyguanosine, a marker of DNA oxidative damage, along with the activation of antioxidant machinery and DNA repair systems, including xeroderma pigmentosum group C (XPC) protein complex and 8-oxoguanine DNA glycosylase 1. HnB also induces the expression of drug-metabolizing enzymes such as CYP1A1, CYP2A6, CYP2B6, and CYP2E, particularly involved in the biotransformation of nicotine and several carcinogenic agents such as aldehydes and polycyclic aromatic hydrocarbons here recorded in the HnB stick smoke. Taken together, these effects, from disruption of redox homeostasis, inflammation, PPAR manipulation along with enhanced bioactivation of neurotoxicants, and upregulation of cMYC protooncogene to impairment of primary cellular defense mechanisms, suggest a possible increased risk of brain cancer. Although the HnB device reduces the emission of tobacco toxicants, our findings indicate that its consumption may carry a risk of potential adverse health effects, especially in non-smokers so far. Further studies are needed to fully understand the long-term effects of these devices.

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Section: Discussionmentioning

confidence: 99%

Effects of unburned tobacco smoke on inflammatory and oxidative mediators in the rat prefrontal cortex

Vivarelli,

Morosini,

Rullo

et al. 2024

Front. Pharmacol.

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“…It is important to highlight that the results presented above link the activation of PPARs receptors in in vitro and in vivo models to the development of obesity and diabetes, due to the interaction, activation, and biological responses (accumulation of lipids, adipogenesis, alteration in carbohydrates metabolism, insulin resistance); mainly with organotin pesticides (TBT and TPT) [21, 34, 43-45, 59, 76], followed by organophosphates (chlorpyrifos and DDT/DDE) [6,9,31,32,37,46,50,61,86]; however, the remaining pesticides such as pyrethroids, carbamates, and others show similar trends in terms of effects on PPARs as initially found for organotin and organophosphates. Therefore, further studies are needed to expand and clarify the mechanism by which pesticides might activate PPARs receptors and cause the development of obesity and diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

“…The study of metabolites derived from pesticides is poorly understood, but for DDE (a metabolite of DDT) in SH-SY5Y cells [31], 3,5,6-trichloropyridinol (TCP) [32] and chlorpyrifos-oxon (CPO) in MCF-7 cells [61], the latter two chlorpyrifos metabolites were reported to have PPARγagonizing effects and to promote adipogenesis. The quizalofop-p-ethyl metabolites studied (quizalofopic acid, tetrahydrofurfuryl alcohol, and 2,3-dihydroxyquinoxaline) appear to have no activity on adipose tissue [39].…”

Section: The Biological Effect Of Ppar Activation In Lipidmentioning

confidence: 99%

“…In the metabolism of lipids in neurons, the metabolite of chlorpyrifos, chlorpyrifos oxon, caused the inhibition of fatty acid amide hydrolase (FAAH), the increase of metabolites of endocannabinoids (eCB), which are agonists of PPARs, as well favored the activation of PPARs in MCF-7 cells and the alteration of lipid metabolism [61].…”

Section: Alteration Of Lipid and Carbohydrate Metabolism Bymentioning

confidence: 99%

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Effect of Pesticides on Peroxisome Proliferator-Activated Receptors (PPARs) and Their Association with Obesity and Diabetes

2023

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Obesity and diabetes mellitus are considered the most important diseases of the XXI century. Recently, many epidemiological studies have linked exposure to pesticides to the development of obesity and type 2 diabetes mellitus. The role of pesticides and their possible influence on the development of these diseases was investigated by examining the relationship between these compounds and one of the major nuclear receptor families controlling lipid and carbohydrate metabolism: the peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ; this was possible through in silico, in vitro, and in vivo assays. The present review aims to show the effect of pesticides on PPARs and their contribution to the changes in energy metabolism that enable the development of obesity and type 2 diabetes mellitus.

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“…Using the U.S. EPA ToxCast database, we demonstrated that much of the OP bioactivity interfered with cytochrome P450 and lipid/steroid metabolism rather than cholinergic signaling (Leung and Meyer 2019). The peroxisome proliferator-activated receptor (PPAR) pathway, a key nuclear receptor regulatory pathway for lipid/steroid metabolism, was found to respond to chlorpyrifos exposure in vitro in a dose-dependent manner (Herriage et al 2022). Additionally, other neuron types such as dopamine (DA) neurons are also vulnerable to chlorpyrifos exposure (Eddins et al 2010; Singh et al 2018; Zhang et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Complementary biological and computational approaches identify distinct mechanisms of chlorpyrifos versus chlorpyrifos oxon induced dopaminergic neurotoxicity

Sammi

Syeda

Conrow

et al. 2022

Preprint

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Organophosphate (OP) pesticides are widely used in agriculture. While acute cholinergic toxicity has been extensively studied, chronic effects on other neurons are less understood. Here, we demonstrated that the OP pesticide chlorpyrifos (CPF) and its oxon metabolite are dopaminergic neurotoxicants in Caenorhabditis elegans. CPF treatment led to inhibition of mitochondrial complex II, II + III, and V in rat liver mitochondria, while CPF oxon did not (complex II + III, and IV inhibition observed only at high doses). While the effect on C. elegans cholinergic behavior was mostly reversible with toxicant washout, dopamine-associated deficits persisted, suggesting dopaminergic neurotoxicity was irreversible. CPF reduced the mitochondrial content in a dose-dependent manner and the fat modulatory genes cyp-35A2 and cyp-35A3 were found to have a key role in CPF neurotoxicity. These findings were consistent with in vitro effects of CPF and CPF oxon on nuclear receptor signaling and fatty acid/steroid metabolism observed in ToxCast assays. Two-way hierarchical analysis revealed in vitro effects on estrogen receptor (ER,) pregnane X receptor (PXR), and peroxisome proliferator-activated receptor gamma (PPAR gamma) pathways as well as neurotoxicity of chlorpyrifos, malathion, and diazinon, while these effects were not detected in malaoxon and diazoxon. Taken together, our study suggests that mitochondrial toxicity and metabolic effects of CPF, but not CPF-oxon, have a key role of CPF neurotoxicity in the low-dose, chronic exposure. Further mechanistic studies are needed to examine mitochondria as a common target for all OP pesticide parent compounds, since this has important implications on cumulative pesticide risk assessment.

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Concentration-dependent effects of chlorpyrifos oxon on peroxisome proliferator-activated receptor signaling in MCF-7 cells

Cited by 12 publications

References 78 publications

Effects of unburned tobacco smoke on inflammatory and oxidative mediators in the rat prefrontal cortex

Effects of unburned tobacco smoke on inflammatory and oxidative mediators in the rat prefrontal cortex

Effect of Pesticides on Peroxisome Proliferator-Activated Receptors (PPARs) and Their Association with Obesity and Diabetes

Complementary biological and computational approaches identify distinct mechanisms of chlorpyrifos versus chlorpyrifos oxon induced dopaminergic neurotoxicity

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