Fruit fly models for assessment of population variability in toxicity
Toxic responses are specific to cell types, and the gene expression patterns of cell types are highly conserved in evolution. The diversity in gene expression among cell types in a single individual is far greater than gene sequence diversity in populations. Thus, any cell type-restricted study using either cell lines or physiological systems such as organoids will fail to capture the full diversity of human exposure risk. Invertebrate organisms such as insects are exempt from most animal regulations and have thousands of cell types, many of which are shared between these organisms and humans. The European Union PrecisionTox project is an international consortium that explores the replacement of traditional mammalian chemical safety testing by comparative toxicology in fruit flies, nematodes, water fleas, clawed frog and zebrafish embryos, and human cell lines.
NIH is participating in a PrecisionTox study that is supplementing comparative toxicology data using more traditional terminal endpoints with data from gene expression and metabolite profiling induced by low subphenotypic doses of chemicals to map conserved AOPs. The study is leveraging fruit fly genetics to inform testing of key human genes and allelic variants, as well as counteracting chemicals that might change susceptibility in people. These data are expected to provide mechanistic insight and feed predictive models useful for regulating groups of chemicals. During 2022 and 2023, institutions participating in the study assembled information on a 250-chemical library, including chemical class, diversity in terms of structure, physicochemical properties, toxicity modes-of-action if known, and database/literature-derived associations with disease pathology, genes, and putative metabolic biomarkers. Harmonized toxicity testing experiments were conducted on about 90 substances, with 54 substances having sufficient comparative toxicology results for a first “phylogenetic toxicity analysis” to allow cross-species extrapolation. RNA expression and metabolite profiling is in progress for the 90-substance set, and the consortium is also conducting genome-wide screenings for genetic variation in toxicity. Study data will be made available in a manner supporting FAIR (findable, accessible, interoperable, and reusable) data standards.
PrecisionTox participating institutions are also engaging with government stakeholders to advance the use of new approach methodologies (NAMs) in chemical regulation. Outcomes of the studies will be applied to support the development of cost-effective NAMs to assess chemical hazard and exposure that can be applied by regulatory bodies and industry.