Metabolomics‐on‐a‐chip approach to study hepatotoxicity of DDT, permethrin and their mixtures

Abstract

Despite the diversity of studies on pesticide toxicities, there is a serious lack of information concerning the toxic effect of pesticides mixtures. Dichlorodiphenyl-trichloroethane (DDT) and permethrin (PMT) are among the most prevalent pesticides in the environment and have been the subject of several toxicological studies. However, there are no data on the toxicity of their mixtures. In this study, we used an approach combining cell culture in microfluidic biochips with gas chromatography-mass spectrometry metabolomics profiling to investigate the biomarkers of toxicity of DDT, PMT and their mixtures. All parameters observed indicated that no significant effect was observed in hepatocytes cultures exposed to low doses (15 μm) of DDT and PMT. Conversely, combined low doses induce moderate oxidative stress and cell death. The toxic signature of high doses of pesticides (150 μm) was illustrated by severe oxidative stress and cell mortality. Metabolomics profiling revealed that hepatocytes exposure to DDT150, PMT150 and DDT150 and PMT150 cause important modulation in intermediates of glutathione pathway and tricarboxylic acid cycle, amino acids and metabolites associated to hepatic necrosis and inflammation (α-ketoglutarate, arginine and 2-hydroxybutyrate). These changes were more striking in the combined group. Finally, DDT150 led to a significant increase of benzoate, decanoate, octanoate, palmitate, stearate and tetradecanoate, which illustrates the estrogen modulation. This study demonstrates the potential of metabolomics-on-a-chip approach to improve knowledge on the mode of action of pesticides.

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants

“…Furthermore, several studies have reported the pro-oxidative properties of some herbicides [151,153,154,221,[373][374][375][376] and chemical families of fungicides (carbamate, benzimidazole, strobilurin, azoles, triazoles [159,[377][378][379][380][381][382][383]) (Table 3). Liver oxidative stress is also reported in animals exposed to a mixture of pesticides [168,193,384] (Tables 1 and 3). Collectively, these data underscore the pro-oxidative properties of insecticides, herbicides, and fungicides.…”

“…Altogether, these findings indicate that pesticides affect several processes that result in oxidative stress: the CYP450 system, mitochondrial respiration, antioxidant pathways, the stress adaptor system, and scavenger ROS activity. Besides oxidative stress, pesticide exposure may lead to NAFLD through their impact on lipid metabolism by (i) modifying fatty acid uptake and efflux [171] and modulating FFA transport as described for insecticides and herbicides, (ii) increasing lipogenesis ( [173,406] (Table 1), (iii) altering oxidation pathways [175]; insecticides, herbicides, and fungicides affect both β-oxidation and lipogenesis (Tables 1 and 2), (iv) interacting with nuclear receptors [416][417][418][419][420][421] involved in the control of metabolism as demonstrated for pyrethroid and neonicotinoid insecticides [176][177][178], and imidazole or triazole fungicides [158,382] or a pesticide mixture [193], but implication in NAFLD is not proven. Some pesticides may ameliorate lipid metabolism.…”

High-Resolution Metabolomic Assessment of Pesticide Exposure in Central Valley, California

“…7 Due to the toxicity of OPs and the persistence of OCs, their use in agriculture has been restricted, and in recent decades, other types of insecticides, including PYRs, have been used more widely. 8 The primary targets of PYRs are the membrane sodium channels, but they also act on potassium, chloride, and calcium channels. 9−11 As a group they are known as axonic excitotoxins as they disturb sodium channels, leading to abnormal neural activity.…”

Tackling Current Biomedical Challenges With Frontier Biofabrication and Organ-On-A-Chip Technologies

“…However, to date, mostly microtissues cultured within OOC systems have been used as inputs for omic analyses—which are generally performed off-chip—while no significant steps have been reported in the integration of biofabricated samples and omics approaches. In particular, OOCs coupled with omics have been developed based on the profiling of the metabolome in microfluidic bioartificial organs with the ability to identify toxicity markers in vitro ( Shintu et al, 2012 ; Lee D. W. et al, 2017 ; Jellali et al, 2018 ). For example, Wang and colleagues created an excellent human organ-on-a-chip system integrating, for the first time, cell engineering as well as drug metabolism and metabolomics to imitate complex human physiology and multi-organ interconnections ( Wang X. et al, 2019 ).…”