The Transcriptional Response of Caenorhabditis elegans to Ivermectin Exposure Identifies Novel Genes Involved in the Response to Reduced Food Intake

Abstract

We have examined the transcriptional response of Caenorhabditis elegans following exposure to the anthelmintic drug ivermectin (IVM) using whole genome microarrays and real-time QPCR. Our original aim was to identify candidate molecules involved in IVM metabolism and/or excretion. For this reason the IVM tolerant strain, DA1316, was used to minimise transcriptomic changes related to the phenotype of drug exposure. However, unlike equivalent work with benzimidazole drugs, very few of the induced genes were members of xenobiotic metabolising enzyme families. Instead, the transcriptional response was dominated by genes associated with fat mobilization and fatty acid metabolism including catalase, esterase, and fatty acid CoA synthetase genes. This is consistent with the reduction in pharyngeal pumping, and consequential reduction in food intake, upon exposure of DA1316 worms to IVM. Genes with the highest fold change in response to IVM exposure, cyp-37B1, mtl-1 and scl-2, were comparably up-regulated in response to short–term food withdrawal (4 hr) independent of IVM exposure, and GFP reporter constructs confirm their expression in tissues associated with fat storage (intestine and hypodermis). These experiments have serendipitously identified novel genes involved in an early response of C. elegans to reduced food intake and may provide insight into similar processes in higher organisms.

Genome-Wide Evaluation of the Interplay between Caenorhabditis elegans and Yersinia pseudotuberculosis during In Vivo Biofilm Formation

“…They include genes associated with fatty acid metabolism (fat-3, fat-7, far-7, and acs-17) and cyp-37B1 and scl-2 (thought to be associated with fat storage). In our study, fat-2 and fat-3 were upregulated and fat-7 downregulated as was the case after exposure to ivermectin (27). However, we have found that a fat-3 deletion mutant is refractory to biofilm formation.…”

“…Since Y. pseudotuberculosis forms biofilm around the head of C. elegans blocking the mouth, it is possible that the worm may respond by inducing genes associated with reduced food uptake. Previously, Laing et al (27) showed that exposure of C. elegans to the nematocidal drug ivermectin results in the induction of many genes associated with starvation. A comparison of the numbers of genes associated with biofilm formation and ivermectin treatment is summarized in Fig.…”

“…However, no obvious differentially expressed candidate toxin genes could be identified from our transcriptome experiments comparing the wild-type Y. pseudotuberculosis with the QS mutants. There is, however, some overlap between worms with biofilm and genes identified as a response to ivermectin exposure (27) which are thought to be a response to reduced food intake (30) as summarized in Fig. 2 and Table S3 in the supplemental material.…”

Adaptive and Specialised Transcriptional Responses to Xenobiotic Stress in Caenorhabditis elegans Are Regulated by Nuclear Hormone Receptors

“…A number of wide-scale studies have been carried out to investigate transcriptional responses of C. elegans to a variety of different chemical exposures, including anthelmintics [39]–[41], insecticides [42], polychlorinated biphenyls [43], vertebrate steroids [44] and juglone [45]. Whilst these studies have identified a number of upregulated transcripts (particularly from the families involved in cellular metabolism) they have usually involved exposures to relatively few compounds.…”

Reliable reference gene selection for quantitative real time PCR in Haemonchus contortus

“…IVM is a macrocyclic lactone, which irreversibly binds to and activates ligand-gated chloride channels, resulting in paralysis of the body wall and pharyngeal muscles [13]. IVM has been shown to induce the expression of a notably different subset of genes in C. elegans, particularly those associated with fat metabolism, thought to reflect a fasting response [14]. The effect of these anthelmintics on the stability of commonly used RGs in H. contortus has not been described.…”