Exposure to chlorpyrifos increases neutral lipid accumulation with accompanying increased de novo lipogenesis and decreased triglyceride secretion in McArdle-RH7777 hepatoma cells

Howell, George; Mulligan, Charlee; Young, Darian; Kondakala, Sandeep

doi:10.1016/j.tiv.2016.01.002

Cited by 24 publications

(41 citation statements)

References 44 publications

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“…In the following we use the H, M, L abbreviations to state high, medium and low concentrations, respectively. The chosen concentrations are in or below the range of the doses tested in immortalized thyrocytes for ETU17 and other cell systems for CPF18. Since humans are usually co-exposed, we also treated the cells with the mixtures of ETU and CPF to evaluate possible additive/synergic effects.…”

Section: Resultsmentioning

confidence: 99%

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Porreca

D’Angelo

Franceschi

et al. 2016

Sci Rep

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In vitro Omics analysis (i.e. transcriptome) is suggested to predict in vivo toxicity and adverse effects in humans, although the causal link between high-throughput data and effects in vivo is not easily established. Indeed, the chemical-organism interaction can involve processes, such as adaptation, not established in cell cultures. Starting from this consideration we investigate the transcriptomic response of immortalized thyrocytes to ethylenthiourea and chlorpyrifos. In vitro data revealed specific and common genes/mechanisms of toxicity, controlling the proliferation/survival of the thyrocytes and unrelated hematopoietic cell lineages. These results were phenotypically confirmed in vivo by the reduction of circulating T4 hormone and the development of pancytopenia after long exposure. Our data imply that in vitro toxicogenomics is a powerful tool in predicting adverse effects in vivo, experimentally confirming the vision described as Tox21c (Toxicity Testing in the 21st century) although not fully recapitulating the biocomplexity of a living animal.

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Section: Resultsmentioning

confidence: 99%

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Porreca

D’Angelo

Franceschi

et al. 2016

Sci Rep

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“…Moreover, acute and chronic exposures to chlorpyrifos have been shown to be associated with increased body weight, altered lipid homeostasis, and increased blood pressure 51–53. Increased fatty acid synthesis and storage have been further substantiated in vitro following chlorpyrifos exposure 54. As a result, it is biologically plausible that in humans, early-life exposures to chlorpyrifos may in fact increase the risk of metabolic disturbances.…”

Section: Crop Production: Pesticidesmentioning

confidence: 99%

Early-life chemical exposures and risk of metabolic syndrome

Long

Holloway

2017

DMSO

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The global prevalence of obesity has been increasing at a staggering pace, with few indications of any decline, and is now one of the major public health challenges worldwide. While obesity and metabolic syndrome (MetS) have historically thought to be largely driven by increased caloric intake and lack of exercise, this is insufficient to account for the observed changes in disease trends. There is now increasing evidence to suggest that exposure to synthetic chemicals in our environment may also play a key role in the etiology and pathophysiology of metabolic diseases. Importantly, exposures occurring in early life (in utero and early childhood) may have a more profound effect on life-long risk of obesity and MetS. This narrative review explores the evidence linking early-life exposure to a suite of chemicals that are common contaminants associated with food production (pesticides; imidacloprid, chlorpyrifos, and glyphosate) and processing (acrylamide), in addition to chemicals ubiquitously found in our household goods (brominated flame retardants) and drinking water (heavy metals) and changes in key pathways important for the development of MetS and obesity.

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“…Following exposure, hepatocytes were washed once with PBS and fixed with 10% buffered formalin for at least 30 minutes prior to ORO staining to measure intracellular neutral lipid accumulation. Intracellular triglyceride levels were measured via commercially available assay (Cayman Chemical) per manufacturer's instructions and expressed as μmol TG/mg protein as previously performed to confirm that significant ORO accumulation is due to increased intracellular triglyceride accumulation …”

Section: Methodsmentioning

confidence: 99%

“…The effect of trans‐nonachlor on free fatty acid uptake/accumulation was determined using Bodipy‐labeled 4,4‐difluoro‐5‐methyl‐4‐bora‐3a,4a‐diaza‐s‐indacene‐3‐dodecanoic acid (BODIPY 500/510 C12; BODIPY‐FA; Molecular Probes) as previously described . Briefly, primary hepatocytes were treated with vehicle (DMSO 0.025%) or trans‐nonachlor (0.2, 2, or 20 μM) for 24 hours in serum free RPMI‐1640 containing fatty acid free BSA (0.5%) with duplicate measurements per individual hepatocyte isolation.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, primary hepatocytes were treated with vehicle (DMSO 0.025%) or trans‐nonachlor (0.2, 2, or 20 μM) for 24 hours in serum free RPMI‐1640 containing fatty acid free BSA (0.5%) with duplicate measurements per individual hepatocyte isolation. Following trans‐nonachlor treatment, cells were washed with PBS then exposed to Bodipy‐labeled dodecanoic acid for 1 minute and 60 minutes to assess saturable, transporter mediated fatty acid uptake and fatty acid accumulation, respectively . At the end of Bodipy‐labeled dodecanoic acid exposure, cells were washed 3 times with ice cold PBS then homogenized in 0.2% SDS.…”

Section: Methodsmentioning

confidence: 99%

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Alterations in cellular lipid metabolism produce neutral lipid accumulation following exposure to the organochlorine compound trans‐nonachlor in rat primary hepatocytes

Howell

McDevitt

Henein

et al. 2018

Environmental Toxicology

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Recent epidemiological studies have revealed significant positive associations between exposure to organochlorine (OC) pesticides and occurrence of the metabolic syndrome and there are a growing number of animal-based studies to support causality. However, the cellular mechanisms linking OC compound exposure and metabolic dysfunction remain elusive. Therefore, the present study was designed to determine if direct exposure to three highly implicated OC compounds promoted hepatic steatosis, the hepatic ramification of the metabolic syndrome. First, the steatotic effect of p,p'-dichlorodiphenyldichloroethylene (DDE), oxychlordane, and trans-nonachlor was determined in freshly isolated rat primary hepatocytes. Exposure to trans-nonachlor significantly increased neutral lipid accumulation as opposed to DDE and oxychlordane. To determine possible mechanisms governing increased fatty acid availability, the effects of trans-nonachlor exposure on fatty acid uptake, de novo lipogenesis, triglyceride secretion, and fatty acid oxidation were explored. Trans-nonachlor did not significantly alter fatty acid uptake. However, insulin-stimulated de novo lipogenesis as well as basal expression of fatty acid synthase, a major regulator of lipogenesis were significantly increased following trans-nonachlor exposure. Interestingly, there was a significant decrease in fatty acid oxidation following trans-nonachlor exposure. This decrease in fatty acid oxidation was accompanied by a slight, but significant increase in oleic acid-induced cellular triglyceride secretion. Therefore, taken together, the present data indicate direct exposure to trans-nonachlor has a more potent pro-steatotic effect than exposure to DDE or oxychlordane. This pro-steatotic effect of trans-nonachlor appears to be predominately mediated via increased de novo lipogenesis and decreased fatty acid oxidation.

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Exposure to chlorpyrifos increases neutral lipid accumulation with accompanying increased de novo lipogenesis and decreased triglyceride secretion in McArdle-RH7777 hepatoma cells

Cited by 24 publications

References 44 publications

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Early-life chemical exposures and risk of metabolic syndrome

Alterations in cellular lipid metabolism produce neutral lipid accumulation following exposure to the organochlorine compound trans‐nonachlor in rat primary hepatocytes

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