Distinct patterns of gene and protein expression elicited by organophosphorus pesticides in Caenorhabditis elegans.
BACKGROUND
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. 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.


RESULTS
After 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.


CONCLUSIONS
Exposure 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.
Lewis
John A
JA
US Army Center for Environmental Health Research, Fort Detrick, MD, USA. john.a.lewis1@us.army.mil
Szilagyi
Maria
M
Gehman
Elizabeth
E
Dennis
William E
WE
Jackson
David A
DA
D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics*; D016000:Cluster Analysis; D004006:Dichlorvos / Q000633:toxicity*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D007306:Insecticides / Q000633:toxicity*; D015767:Mefloquine / Q000633:toxicity; D020411:Oligonucleotide Array Sequence Analysis; D009943:Organophosphorus Compounds / Q000633:toxicity*; D020543:Proteome / Q000235:genetics; D018510:RNA, Helminth / Q000235:genetics
D007306:Insecticides; D009943:Organophosphorus Compounds; D020543:Proteome; D018510:RNA, Helminth; D004006:Dichlorvos; C002698:fenamiphos; D015767:Mefloquine