Effects of mipafox, paraoxon, chlorpyrifos and its metabolite chlorpyrifos-oxon on the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells.
Chlorpyrifos (CPS) is an organophosphorus compound (OP) capable of causing well-known cholinergic and delayed syndromes through the inhibition of acetylcholinesterase and Neuropathy Target Esterase (NTE), respectively. CPS is also able to induce neurodevelopmental toxicity in animals. NTE is codified by the Pnpla6 gene and plays a central role in differentiation and neurodifferentiation. We tested, in D3 mouse embryonic stem cells under differentiation, the effects of the NTE inhibition by the OPs mipafox, CPS and its main active metabolite chlorpyrifos-oxon (CPO) on the expression of genes Vegfa, Bcl2, Amot, Nes and Jun, previously reported to be under- or overexpressed after Pnpla6 silencing in this same cellular model. Mipafox did not significantly alter the expression of such genes at concentrations that significantly inhibited NTE. However, CPS and CPO at concentrations that caused NTE inhibition at similar levels to mipafox statistically and significantly altered the expression of most of these genes. Paraoxon (another OP with capability to inhibit esterases but not NTE) caused similar effects to CPS and CPO. These findings suggest that the molecular mechanism for the neurodevelopmental toxicity induced by CPS is not based on NTE inhibition, and that other unknown esterases might be potential targets of neurodevelopmental toxicity.
Toxicology and Chemical Safety Unit, Bioengineering Institute, Miguel Hernández University, Avenida de la Universidad s/n, 03202, Elche, Spain. Electronic address: msogorb@umh.es.
Miguel A
MA
Sogorb
Toxicology and Chemical Safety Unit, Bioengineering Institute, Miguel Hernández University, Avenida de la Universidad s/n, 03202, Elche, Spain.
Encarnación
E
Fuster
Toxicology and Chemical Safety Unit, Bioengineering Institute, Miguel Hernández University, Avenida de la Universidad s/n, 03202, Elche, Spain.
Eva
E
Del Río
Toxicology and Chemical Safety Unit, Bioengineering Institute, Miguel Hernández University, Avenida de la Universidad s/n, 03202, Elche, Spain.
Jorge
J
Estévez
Toxicology and Chemical Safety Unit, Bioengineering Institute, Miguel Hernández University, Avenida de la Universidad s/n, 03202, Elche, Spain.
Eugenio
E
Vilanova
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D004390:Chlorpyrifos / Q000031:analogs & derivatives* / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D007531:Isoflurophate / Q000031:analogs & derivatives* / Q000633:toxicity; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D010261:Paraoxon / Q000633:toxicity*
D015415:Biomarkers; D007531:Isoflurophate; C005238:mipafox; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D004390:Chlorpyrifos; D010261:Paraoxon
Chlorpyrifos; Differentiation; Embryonic stem cell; Neurodevelopmental toxicity; Neuropathy target esterase; Pnpla6