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1.
Toxicol In Vitro ; 28(5): 715-21, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24486155

ABSTRACT

Organophosphate (OP) compounds are used as insecticides, acaricides, and chemical agents and share a common neurotoxic mechanism of action. The biochemical alterations leading to many of the deleterious effects have been studied in neuronal cell lines, however, non-neuronal toxic effects of OPs are far less well characterized in vitro, and specifically in cell lines representing oral routes of exposure. To address this void, the human salivary gland (HSG) cell line, representing likely interactions in the oral cavity, was exposed to the representative OP paraoxon (PX; O,O-diethyl-p-nitrophenoxy phosphate) over a range of concentrations (0.01-100 µM) and analyzed for cytotoxicity. PX induced cytotoxicity in HSG cells at most of the exposure concentrations as revealed by MTT assay, however, the release of LDH only occurred at the highest concentration of PX tested (100 µM) at 48 h. Slight increases in cellular ATP levels were measured in PX-exposed (10 µM) HSG cells at 24 h. Exposing HSG cells to 10 µM PX also led to an increase in DNA fragmentation prior to loss of cellular membrane integrity implicating reactive oxygen species (ROS) as a trigger of toxicity. The ROS genes gss, gstm2, gstt2 and sod2 were upregulated, and the presence of superoxide following 10 µM PX exposure was determined via dihydroethidium fluorescence studies further implicating PX-induced oxidative stress in HSG cells.


Subject(s)
Cholinesterase Inhibitors/toxicity , Insecticides/toxicity , Oxidative Stress , Paraoxon/toxicity , Salivary Glands/cytology , Acetylcholinesterase/metabolism , Adenosine Triphosphate/metabolism , Cell Line , Cell Survival/drug effects , DNA Fragmentation , Eating , Glutathione Synthase/genetics , Glutathione Transferase/genetics , Humans , Reactive Oxygen Species/metabolism , Superoxide Dismutase/genetics
2.
Aquat Toxicol ; 100(1): 101-11, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20701988

ABSTRACT

Organophosphate pesticides (OPs) are environmental toxicants known to inhibit the catalytic activity of acetylcholinesterase (AChE) resulting in hypercholinergic toxicity symptoms. In developing embryos, OPs have been hypothesized to affect both cholinergic and non-cholinergic pathways. In order to understand the neurological pathways affected by OP exposure during embryogenesis, we developed a subacute model of OP developmental exposure in zebrafish by exposing embryos to a dose of the OP metabolite chlorpyrifos-oxon (CPO) that is non-lethal and significantly inhibited AChE enzymatic activity compared to control embryos (43% at 1 day post-fertilization (dpf) and 11% at 2dpf). Phenotypic analysis of CPO-exposed embryos demonstrated that embryonic growth, as analyzed by gross morphology, was normal in 85% of treated embryos. Muscle fiber formation was similar to control embryos as analyzed by birefringence, and nicotinic acetylcholine receptor (nAChR) cluster formation was quantitatively similar to control embryos as analyzed by α-bungarotoxin staining. These results indicate that partial AChE activity during the early days of zebrafish development is sufficient for general development, muscle fiber, and nAChR development. Rohon-Beard (RB) sensory neurons exhibited aberrant peripheral axon extension and gene expression profiling suggests that several genes responsible for RB neurogenesis are down-regulated. Stability of CPO in egg water at 28.5 °C was determined by HPLC-UV-MS analysis which revealed that the CPO concentration used in our studies hydrolyzes in egg water with a half-life of 1 day. The result that developmental CPO exposure affected RB neurogenesis without affecting muscle fiber or nAChR cluster formation demonstrates that zebrafish are a strong model system for characterizing subtle neurological pathologies resulting from environmental toxicants.


Subject(s)
Chlorpyrifos/analogs & derivatives , Insecticides/toxicity , Sensory Receptor Cells/drug effects , Zebrafish/growth & development , Animals , Chlorpyrifos/toxicity , Dose-Response Relationship, Drug , Embryo, Nonmammalian/abnormalities , Embryo, Nonmammalian/drug effects , Embryo, Nonmammalian/ultrastructure , Embryonic Development/drug effects , Gene Expression/drug effects , Neurogenesis/drug effects , Neurogenesis/genetics , Neuromuscular Junction/drug effects , Neuromuscular Junction/growth & development , Organophosphates/toxicity , Sensory Receptor Cells/ultrastructure , Toxicity Tests , Water Pollutants, Chemical/toxicity , Zebrafish/abnormalities , Zebrafish/embryology
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