Unanticipated differences in the rat plasma metabolome...

Unanticipated Differences In the Rat Plasma Metabolome of Genistein and Daidzein

Gina Montoyan1, Bennard van Ravenzwaay 2, Walburga Seefelder 1, Volker Haake 3, Thomas Stroheker 1, Hennicke Kamp 3

1 Société des Produits Nestlé S.A., Lausanne, Switzerland

2 Environmental Sciences Consulting, Altrip, Germany

3 BASF Metabolome Solutions GmbH, Berlin, Germany

Genistein (GEN) and daidzein (DAI) are soy isoflavones known for their interaction with estrogen receptors, exhibiting both health benefits and concerns in humans. In this study, we conducted 28-day oral studies in male and female Wistar rats to elucidate (1) changes in metabolites, (2) compare their metabolomes with other compounds, and (3) identify toxicological modes of action (MoA).

Dose levels for GEN were 1000 and 300 mg/kg bw by gavage and 1000 and 300 ppm (via diet). DAI gavage dose levels were 1000 and 100 mg/kg bw/day. Results were evaluated using the MetaMap®Tox database. Both compounds demonstrated metabolome profiles associated with estrogenic profiles and compounds, predominantly in females. However, the metabolomes were compound-specific with relatively few common metabolite changes. Notably, there were no relevant matches between any GEN and any DAI treatment group indicating that both compounds are substantially different from metabolome perspective.

Ranking of the metabolome patterns for GEN and DAI with ≥ 1000 compounds in the MetaMap®Tox database revealed correlations with estrogenic and other hormonally active compounds. Furthermore, the metabolome of GEN-treated females correlated best with Cabergoline, a dopamine D2 receptor agonist, while DAI females with tamoxifen and diethylstilbestrol, suggesting that even their estrogenic activity may be different. Beyond estrogenic effects, the high dose (HD) DAI metabolome indicated altered fatty acid metabolism associated with PPAR-α activation, while GEN showed indications of ethanolamine-like liver effects. Dose levels without estrogenic effects for GEN were 1000 and 100 mg/kg bw/day for males and females respectively, there were no estrogenic effects in the feeding studies. For DAI, the no estrogenic effect level was 300 mg/kg bw/day for males and 100 mg/kg bw/day for females, suggesting that DAI may be a more potent estrogen than GEN in rats.

Key words: Metabolomics, Genistein, Daidzein, Estrogens