Phenomics, transcriptomics and metabolomics for identifying concentration-dependent chemical interactions and understanding the mechanistic basis of the mixture toxicity
Konferensbidrag (offentliggjort, men ej förlagsutgivet), 2019

The prevalence of mixtures of synthetic and natural chemicals in the environment is a growing concern for public health and environmental effects. Currently, most chemical legislations are based on the risk assessments carried out on individual substances and theoretical estimates of combination effect. However, exposure to multi-component mixtures may stimulate unpredicted overall toxic responses due to interactions, where interactions were scored as deviations from the independent action model. In our project, we investigated the frequency and magnitude of interactions in mixtures of five compounds - NaCl, HgCl2, paraquat, rapamycin, clotrimazole - with relatively known specific mode of action. Growth effects by all-combination pair-wise mixtures spanning a wide concentration range were investigated by employing high-resolution yeast phenomics. The baker’s/brewer’s yeast Saccharomyces cerevisiae and the marine yeast Debaryomyces hansenii are used in this study to identify evolutionary conserved mixture effects, with the aim to identify generic responses of relevance to a vast array of organisms. Our results clearly show that both synergistic and antagonistic relationships exist among the tested chemicals and some of these relationships are concentration-dependent. Evolutionary conserved interactions on the level of rate of growth were found for salt and rapamycin (synergy) as well as for salt and paraquat (antagonism). The mechanistic basis of the chemical interactions identified in our study was investigated by transcriptomics and metabolomics. As one example, we observed that several genes with symporter activity and with cation transmembrane transporter activity is downregulated in salt plus paraquat mixtures, while the expression of genes that are related to cofactor-dependent metabolic pathways is stimulated. We believe that the repression of symporter and ion transmembrane transport activity reduces paraquat entry to the yeast cells and thereby reduces its toxic response when combined with salt. On the other hand, upregulation of several of the genes (such as PGI1, PFK1, FBA1, and CDC19) related to cofactor-dependent metabolic pathways boost yeast fermentative activity. Since paraquat induces the production of reactive oxygen species (ROS) via respiration, a shift from aerobic respiration to anaerobic fermentation can reduce formation of ROS, thus reduces oxidative stress by paraquat.

Mixture toxicity

Debaryomyces hansenii

Saccharomyces cerevisiae

Phenomics

Phenotypic evaluation

Chemical interactions

Independent Action model

Yeast

Metabolomics

Transcriptomics

Oxidative stress

Författare

Vaskar Mukherjee

Chalmers, Biologi och bioteknik, Industriell bioteknik

Göteborgs universitet

Anders Pedersen

Swedish NMR Center

Göteborgs universitet

Daniel Malmodin

Göteborgs universitet

Swedish NMR Center

Thomas Backhaus

Göteborgs universitet

Anders Blomberg

Göteborgs universitet

29th International Conference on Yeast Genetics and Molecular Biology
Gothenburg, Sweden,

Fundament

Grundläggande vetenskaper

Ämneskategorier

Annan biologi

Farmakologi och toxikologi

Bioinformatik och systembiologi

Miljövetenskap

Genetik

Styrkeområden

Livsvetenskaper och teknik (2010-2018)

Mer information

Skapat

2019-10-01