Application of a skin and liver Chip2 microphysiological model to investigate the route-dependent toxicokinetics and toxicodynamics of consumer-relevant doses of genistein

Abstract

The HUMMIC skin–liver Chip2 microphysiological system using EpiDerm™ and HepaRG and stellate liver spheroids was used to evaluate the route-specific metabolism and toxicodynamic effects of genistein. Human-relevant exposure levels were compared: 60 nM representing the plasma concentration expected after topical application of a cosmetic product and 1 μM representing measured plasma concentrations after ingesting soya products. Genistein was applied as single and repeated topical and/or systemic doses. The kinetics of genistein and its metabolites were measured over 5 days. Toxicodynamic effects were measured using transcriptional analyses of skin and liver organoids harvested on Days 2 and 5. Route-specific differences in genistein's bioavailability were observed, with first-pass metabolism (sulfation) occurring in the skin after topical application. Only repeated application of 1 μM, resembling daily oral intake of soya products, induced statistically significant changes in gene expression in liver organoids only. This was concomitant with a much higher systemic concentration of genistein which was not reached in any other dosing scenario. This suggests that single or low doses of genistein are rapidly metabolised which limits its toxicodynamic effects on the liver and skin. Therefore, by facilitating longer and/or repeated applications, the Chip2 can support safety assessments by linking relevant gene modulation with systemically available parent or metabolite(s). The rate of metabolism was in accordance with the short half-life observed in in vivo in humans, thus supporting the relevance of the findings. In conclusion, the skin–liver Chip2 provides route-specific information on metabolic fate and toxicodynamics that may be relevant to safety assessment.