Dichlorvos exposure results in large scale disruption of energy metabolism in the liver of the zebrafish, Danio rerio.
BACKGROUND
Exposure to dichlorvos (DDVP), an organophosphorus pesticide, is known to result in neurotoxicity as well as other metabolic perturbations. However, the molecular causes of DDVP toxicity are poorly understood, especially in cells other than neurons and muscle cells. To obtain a better understanding of the process of non-neuronal DDVP toxicity, we exposed zebrafish to different concentrations of DDVP, and investigated the resulting changes in liver histology and gene transcription.


RESULTS
Functional enrichment analysis of genes affected by DDVP exposure identified a number of processes involved in energy utilization and stress response in the liver. The abundance of transcripts for proteins involved in glucose metabolism was profoundly affected, suggesting that carbon flux might be diverted toward the pentose phosphate pathway to compensate for an elevated demand for energy and reducing equivalents for detoxification. Strikingly, many transcripts for molecules involved in β-oxidation and fatty acid synthesis were down-regulated. We found increases in message levels for molecules involved in reactive oxygen species responses as well as ubiquitination, proteasomal degradation, and autophagy. To ensure that the effects of DDVP on energy metabolism were not simply a consequence of poor feeding because of neuromuscular impairment, we fasted fish for 29 or 50 h and analyzed liver gene expression in them. The patterns of gene expression for energy metabolism in fasted and DDVP-exposed fish were markedly different.


CONCLUSIONS
We observed coordinated changes in the expression of a large number of genes involved in energy metabolism and responses to oxidative stress. These results argue that an appreciable part of the effect of DDVP is on energy metabolism and is regulated at the message level. Although we observed some evidence of neuromuscular impairment in exposed fish that may have resulted in reduced feeding, the alterations in gene expression in exposed fish cannot readily be explained by nutrient deprivation.
ORISE Postdoctoral Fellow, Fort Detrick, MD, 21702, USA. Tri.Bui-Nguyen@fda.hhs.gov.|Current address: US Food and Drug Administration, Silver Spring, MD, 20993, USA. Tri.Bui-Nguyen@fda.hhs.gov.
Tri M
TM
Bui-Nguyen
Excet, Inc., Springfield, VA, 22151, USA. christine.e.baer2.ctr@mail.mil.
Christine E
CE
Baer
US Army Center for Environmental Health Research, Fort Detrick, MD, 21702, USA. john.a.lewis5.civ@mail.mil.
John A
JA
Lewis
Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, 95616, USA. mryang@ucdavis.edu.
Dongren
D
Yang
Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, 95616, USA. pjlein@ucdavis.edu.
Pamela J
PJ
Lein
US Army Center for Environmental Health Research, Fort Detrick, MD, 21702, USA. david.a.jackson17.civ@mail.mil.
David A
DA
Jackson
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D050260:Carbohydrate Metabolism / Q000235:genetics; D002802:Cholinesterases / Q000378:metabolism; D016000:Cluster Analysis; D004006:Dichlorvos / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007306:Insecticides / Q000633:toxicity*; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*
D007306:Insecticides; D017382:Reactive Oxygen Species; D004006:Dichlorvos; D002802:Cholinesterases