title: Systems Biology Approach Reveals a Calcium-Dependent Mechanism for Basal Toxicity in Daphnia magna.
abstract: The expanding diversity and ever increasing amounts of man-made chemicals discharged to the environment pose largely unknown hazards to ecosystem and human health. The concept of adverse outcome pathways (AOPs) emerged as a comprehensive framework for risk assessment. However, the limited mechanistic information available for most chemicals and a lack of biological pathway annotation in many species represent significant challenges to effective implementation of this approach. Here, a systems level, multistep modeling strategy demonstrates how to integrate information on chemical structure with mechanistic insight from genomic studies, and phenotypic effects to define a putative adverse outcome pathway. Results indicated that transcriptional changes indicative of intracellular calcium mobilization were significantly overrepresented in Daphnia magna (DM) exposed to sublethal doses of presumed narcotic chemicals with log Kow ≥ 1.8. Treatment of DM with a calcium ATPase pump inhibitor substantially recapitulated the common transcriptional changes. We hypothesize that calcium mobilization is a potential key molecular initiating event in DM basal (narcosis) toxicity. Heart beat rate analysis and metabolome analysis indicated sublethal effects consistent with perturbations of calcium preceding overt acute toxicity. Together, the results indicate that altered calcium homeostasis may be a key early event in basal toxicity or narcosis induced by lipophilic compounds.
authors.affiliation: Centre for Computational Biology and Modelling, Institute for Integrative Biology, University of Liverpool , L69 7ZB Liverpool, United Kingdom.
authors.forename: Philipp
authors.initials: P
authors.lastname: Antczak
authors.affiliation: School of Biosciences, University of Birmingham , B15 2TT Birmingham, United Kingdom.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.affiliation: Assam University , Silchar 788011, India.
authors.forename: Anirudha
authors.initials: A
authors.lastname: Giri
authors.affiliation: School of Biosciences, University of Birmingham , B15 2TT Birmingham, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Michelangeli
authors.affiliation: School of Biosciences, University of Birmingham , B15 2TT Birmingham, United Kingdom.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Viant
authors.affiliation: School of Pharmacy and Chemistry, Liverpool John Moores University , Liverpool L3 3AF, United Kingdom.
authors.forename: Mark T D
authors.initials: MT
authors.lastname: Cronin
authors.affiliation: Nutritional Sciences and Toxicology & Berkeley Institute of the Environment, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Vulpe
authors.affiliation: Centre for Computational Biology and Modelling, Institute for Integrative Biology, University of Liverpool , L69 7ZB Liverpool, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Falciani
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003621:Daphnia / Q000187:drug effects* / Q000235:genetics; D004785:Environmental Pollutants / Q000633:toxicity*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D015233:Models, Statistical; D049490:Systems Biology; D019284:Thapsigargin / Q000494:pharmacology; D018675:Toxicity Tests; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004785:Environmental Pollutants; D019284:Thapsigargin; D002118:Calcium