Abstract

Ochratoxins are a group of nephrotoxins produced by a variety of moulds and
were first described in 1965 [1]. Dietary exposure to ochratoxins represents a
serious health issue and has been associated with several human and animal
diseases including porcine nephropathy, Human Endemic Nephropathies and
urinary tract tumours in humans.
More than 20 years ago, ochratoxin A (OTA) - the most prominent member of
this toxin family - was shown to be carcinogenic in rodents and since then
extensive research has been performed in order to investigate whether OTA
acts by a DNA reactive mode of action. Only recently, this theory has been
conclusively disproven and a non-genotoxic mechanism is currently widely
accepted for renal toxicity and carcinogenicity of OTA.
The work presented in this thesis contributed to this field of science in various
ways. First of all, new renal in vitro models were established and existing
models were improved for the investigation of renal ochratoxin toxicity. Using
these models, the in vitro effects of various OTA exposure scenarios were
investigated and endpoints included amongst others general cytotoxicity, cell
cycle analysis, protein binding and toxin transport. In all of these studies,
distinct species- and sex-differences were observed which mirrored the
observed effects in vivo described in literature. Furthermore, the differential
toxicity of ochratoxin group members was investigated, the results of which
inferred a need for specific detection of OTA and OTB. Due to the lack of such a
detection tool, a new, highly specific and sensitive OTB-ELISA was successfully
developed based on an OTB-specific monoclonal antibody produced and
characterised in our laboratory. This tool allows screening of OTB in food and
feed products, which will further improve detection and risk assessment.
All of these studies contributed to the elucidation of the underlying mechanisms
of ochratoxin toxicity. Therefore, this thesis can be seen as a fundamental part
of a paradigm change on our understanding of how ochratoxins exert their
harmful long-term effects in humans and animals, thus elucidating the
ochratoxin enigma.