Toxicology

Chemicals are essential in modern working environments. To avoid toxic exposures a careful risk evaluation of chemicals is required. Ideally, risk evaluation is based on precise knowledge by which mechanisms toxic chemicals cause adverse effects. For this purpose a close cooperation and workflow between four research groups, the research group ‘SysTox’ and the networking group ‘NBTox’ and two junior research groups (LivTox, CellTox) has been established.

A frequently applied form of cooperation within the Department of Toxicology is generation of time-resolved, concentration-dependent, quantitative data by the LivTox, NBTox and CellTox groups, which are used for model simulations by the SysTox group. In return the SysTox group supports the three groups by functional imaging based on two-photon and confocal microscopy and provides the required model simulations. This lead to a deeper understanding of complex interactions at several organisation levels of cells and tissues and how they can be disturbed by chemicals to cause adverse health effects. Examples are novel mechanisms in the field of hepatotoxicity and liver physiology (Zeigerer et al., 2012; Vartak et al., 2016), test systems for neurotoxicity testing (Krug et al., 2013), choline and lipid metabolism (Stewart et al., 2012) as well as genome-wide and transcriptional network characteristics (Godoy et al., 2015) in relation to dedifferentiation and disturbed tissue functionality.

Besides our activity in basic research and test system development, the Department of Toxicology is involved in the establishment of occupational threshold values by its membership and active contribution to the MAK commission (DFG, Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area), AGS (Committee for Hazardous Substances of the German Federal Ministry of Labour and Social Affairs), SCOEL (Scientific Committee on Occupational Exposure Limit Values of the European Commission), SCCS (Scientific Committee on Consumer Safety) and in European projects on toxic risk evaluation, such as EU-ToxRisk.

Externally funded junior teams

Recently, three postdocs of the Systems Toxicology group obtained BMBF as well as EU funding to lead independent junior teams, which closely cooperate within the Toxicology department:

Nachiket Vartak (BMBF funded)
– Functional imaging of hepatic transport mechanisms
– Systems modeling of lipid droplet formation

Ahmed Ghallab (BMBF funded)
– Systems modeling of hepatic metabolism in liver diseases
– Control mechanisms of liver regeneration

Raymond Reif (EU funded)
– Two-photon based intravital imaging

Central scientific services

The four research groups are supported by central scientific services with basic technologies and instruments, such as analytical chemistry, cell culture, mouse facility, flow cytometry and gene expression (organised by the Immunology Department), a study centre as well as occupational medicine service, responsible e.g. for IfADo’s tissue and blood banking. This support is essential for the progress of the toxicology research. Techniques provided by the central scientific services are included into almost all publications.

References1

Vartak N, Damle-Vartak A, Richter B, Dirsch O, Dahmen U, Hammad S, Hengstler JG: Cholestasis-induced adaptive remodeling of interlobular bile ducts. Hepatology 63: 951-964 (2016)

Godoy P, Schmidt-Heck W, Natarajan K, Lucendo-Villarin B, Szkolnicka D, Asplund A, Björquist P, Widera A, Stöber R, Campos G, Hammad S, Sachinidis A, Chaudhari U, Damm G, Weiss TS, Nüssler A, Synnergren J, Edlund K, Küppers-Munther B, Hay DC, Hengstler JG. Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells. J Hepatol 3: 934-942 (2015)

Krug AK, Kolde R, Gaspar JA, Rempel E, Marchan R, van Thriel C, Hengstler JG, Rahnenführer J: Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol 87: 123-143 (2013)

Stewart JD, Marchan R, Lesjak MS, Lambert J, Hergenröder R, Ellis JK, Lau C-H, Hengstler JG: Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis. Proc Natl Acad Sci USA 109: 8155-8160 (2012)

Zeigerer A, Gilleron J, Bogorad RL, Marsico G, Nonaka H, Seifert S, Epstein-Barash H, Kuchimanchi S, Peng CG, Ruda VM, Del Conte-Zerial P, Hengstler JG, Kalaidzidis Y, Koteliansky V, Zerial M.: Rab5 is necessary for the biogenesis of the endolysosomal system in vivo. Nature 485(7399): 465-470 (2012)

1underlined: members of the Toxicology group