Abstract
BackgroundThe wide use of organophosphorus (OP) pesticides makes them an important public health concern. Persistent effects of exposure and the mechanism of neuronal degeneration are continuing issues in OP toxicology. To elucidate early steps in the mechanisms of OP toxicity, we studied alterations in global gene and protein expression in Caenorhabditis elegans exposed to OPs using microarrays and mass spectrometry. We tested two structurally distinct OPs (dichlorvos and fenamiphos) and employed a mechanistically different third neurotoxicant, mefloquine, as an out-group for analysis. Treatment levels used concentrations of chemical sufficient to prevent the development of 10%, 50% or 90% of mid-vulval L4 larvae into early gravid adults (EGA) at 24 h after exposure in a defined, bacteria-free medium.ResultsAfter 8 h of exposure, the expression of 87 genes responded specifically to OP treatment. The abundance of 34 proteins also changed in OP-exposed worms. Many of the genes and proteins affected by the OPs are expressed in neuronal and muscle tissues and are involved in lipid metabolism, cell adhesion, apoptosis/cell death, and detoxification. Twenty-two genes were differentially affected by the two OPs; a large proportion of these genes encode cytochrome P450s, UDP-glucuronosyl/UDP-glucosyltransferases, or P-glycoproteins. The abundance of transcripts and the proteins they encode were well correlated.ConclusionExposure to OPs elicits a pattern of changes in gene expression in exposed worms distinct from that of the unrelated neurotoxicant, mefloquine. The functional roles and the tissue location of the genes and proteins whose expression is modulated in response to exposure is consistent with the known effects of OPs, including damage to muscle due to persistent hypercontraction, neuronal cell death, and phase I and phase II detoxification. Further, the two different OPs evoked distinguishable changes in gene expression; about half the differences are in genes involved in detoxification, likely reflecting differences in the chemical structure of the two OPs. Changes in the expression of a number of sequences of unknown function were also discovered, and these molecules could provide insight into novel mechanisms of OP toxicity or adaptation in future studies.
Highlights
The wide use of organophosphorus (OP) pesticides makes them an important public health concern
We developed an exposure protocol for comparing the effects of different toxicants with varying mechanisms of action based on the developmental arrest displayed by stressed C. elegans worms
Using this technique in conjunction with genomic and proteomic analysis, we identified changes in expression of a group of genes and proteins that are consistent with muscle regeneration or repair resulting from mechanical damage during hypercontraction of muscle in OP exposed worms
Summary
The wide use of organophosphorus (OP) pesticides makes them an important public health concern. Persistent effects of exposure and the mechanism of neuronal degeneration are continuing issues in OP toxicology. The wide use of organophosphorus (OP) based pesticides and unresolved issues in their toxicity, including the causes of persistent and off-target effects and the mechanisms of neuronal degeneration, make them an important concern for public health. The principal risk of toxicity from OPs and other AChE inhibitors occurs after high level, acute exposures when death from respiratory failure may rapidly ensue; less severe exposures may cause salivation, lacrimation, incontinence, and convulsions followed by paralysis potentially resulting in death (reviewed in [6,7]). Organophosphate induced delayed polyneuropathy (OPIDP) is a delayed syndrome (7–21 days after exposure) that is characterized by numbness, weakness, and paresthesia in the limbs and degeneration of peripheral nerves and central nervous system myelin sheaths; inhibition of NTE is thought to underlie OPIDP (reviewed in [1,8,9]). Chronic neurological and neuropsychiatric effects–some of which may persist for years–and developmental neuro-behavioral effects have been described [10,11,12]
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