Predictive liver lipid biomarker signature of Acetyl-coenzyme A carboxylase inhibitor related developmental toxicity in non-pregnant female Han Wistar rats – Lipidomics biomarker discovery and validation

Abstract

IntroductionAcetyl-coenzyme A carboxylase (ACCase) inhibition is an attractive herbicide target. However, issues with fetal developmental toxicity identified at the late stages of the development process can halt progression of previously promising candidates. ObjectivesTo select and verify predictive lipid biomarkers of ACCase inhibition activity in vivo using liver samples obtained from early stage 7 day repeat dose studies in non-pregnant female Han Wistar rats that could be translated to developmental toxicity endpoints discovered during late-stage studies to provide an early screening tool. MethodsLiver samples from eight rat repeat dose studies, exposed to six ACCase inhibitors from three different chemistries and one alternative mode of action (MoA) that also perturbs lipid biochemistry, were analysed using liquid chromatography – high resolution accurate mass – mass spectrometry. Multivariate and univariate data analysis methods were used for biomarker discovery and validation. ResultsA biomarker signature consisting of sixteen lipids biomarkers were selected. Verification of the signature as indicative of ACCase inhibition was established by demonstrating consistent perturbations in the biomarkers using two different ACCase inhibitor chemistries and the lack thereof with an alternate MoA. The fold change profile pattern was predictive of which test substance doses would or would not cause developmental toxicity. ConclusionA strategy for selecting and verifying a robust signature of lipid biomarkers for predicting a toxicological end point has been described and demonstrated. Differences in lipidomic profiles correlated with developmental toxicity suggesting that indicators of a molecular initiation event resulting in pup developmental toxicity can be predicted from short term, toxicity studies conducted in non-pregnant adult female Han Wistar rats.