Abstract
Pharmaceuticals are not currently tested for transgenerational and epigenetic side effects. The use of vertebrates as preclinical research models is limited by their long generation times, low numbers of progeny and ethical concerns. In contrast, invertebrates such as insects breed rapidly, produce many offspring and are more ethically acceptable, allowing them to be used for high-throughput screening. Here, we established Tribolium castaneum as a model to screen for the effect of drugs on complex fitness parameters and the expression of epigenetic regulatory genes. We tested diets supplemented with the psychoactive drug valproic acid (VPA), which is a histone deacetylase inhibitor, or the antioxidant curcumin, which is a histone acetyltransferase inhibitor. We found that VPA delayed development, reduced longevity, and increased female body weight compared to a control diet. Fertility and fecundity declined and the expression of epigenetic regulatory genes was induced in the untreated F1 generation. In contrast, curcumin did not affect development or body weight, but it increased longevity, caused a significant reduction in fertility, and induced the expression of epigenetic regulatory genes mostly in the treated F0 generation. VPA and curcumin administered to vertebrate models have similar effects to those we observed in T. castaneum, confirming that this beetle is potentially useful as an alternative model to screen for the epigenetic effect of drugs. T. castaneum also provides a valuable early warning system for transgenerational epigenetic risk factors that are difficult to detect in mammals.
Abbreviations
DPH, diphenhydramine; HAT, histone acetyltransferase; HDAC, histone deacetylase; KAT, lysine acetyltransferase; MBD, methyl-CpG binding domain protein; Mt, methyltransferase; Nap1, nucleosome assembly protein 1; Sap, Sin3A-associated protein; Sin3A, SIN3 transcription regulator family member A; Sir, sirtuin; SIRT, sirtuin; VPA, valproic acid
Keywords
Curcumin; Drug development; Epigenetics; Insect models; Preclinical research; Tribolium castaneum; Valproic acid
Citation: Linda Bingsohna, Eileen Knorr, Andreas Vilcinskas The model beetle Tribolium castaneum can be used as an early warning system for transgenerational epigenetic side effects caused by pharmaceuticals doi:10.1016/j.cbpc.2016.03.002
Received: 21 November 2015 Revised: 25 February 2016 Accepted: 9 March 2016 Available online: 10 March 2016
Copyright: © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Competing interest
The authors declare that they have no competing interests.
Author contributions
LB performed all experiments and data analyses. EK introduced Tribolium handling. LB and AV conceived the study and drafted parts of the manuscript. All authors read and approved the manuscript.
Acknowledgments
The authors acknowledge financial support from the Hessen State Ministry of Higher Education, Research and the Arts (HMWK) via the collaborative research projects granted under the LOEWE Centers for “Insect Biotechnology and Bioresources” and “Translational Pharmaceutical Research”. The authors thank Dr. Richard M. Twyman for editing the manuscript and Prof. Dr. Michael Parnham (Fraunhofer Institute for Molecular Biology and Applied Ecology) for providing samples of VPA and curcumin.
