Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats

BACKGROUND Ground corncob animal bedding and corn food products contain substances that disrupt endocrine function in rats. The disruptors were identified as isomeric mixtures of tetrahydrofurandiols (THF-diols; 9,12-oxy-10,13-dihydroxyoctadecanoic acid and 10,13-oxy-9,12-dihydroxyoctadecanoic acid) and leukotoxindiols (LTX-diols; 9,10-dihydroxy-12-octadecenoic acid and 12,13-dihydroxy-9-octadecenoic acid). The authentic compounds blocked sexual behavior in male rats and estrous cyclicity in female rats at oral doses of 2 ppm. OBJECTIVES To define the lowest observed adverse effect level (LOAEL) for the THF-diols and LTX-diols in rats, we examined the nature of their interaction (additive or synergistic) and quantified the concentration of THF-diols in rat tissues. METHODS Adult male and female rats were provided drinking solutions containing various doses of THF-diols and/or LTX-diols, and we evaluated their effects on male sexual behavior and female estrous cyclicity. Tissues were collected for THF-diol determination by gas chromatography-mass spectrometry. RESULTS The LOAEL for THF-diols and LTX-diols for blocking estrous cyclicity was 0.5-1.0 ppm and 0.2-0.5 ppm, respectively. Higher concentrations (1-2 ppm) of THF-diols were required to block male sexual behavior. Combination studies with subthreshold doses of 0.05 ppm THF-diols plus 0.05 ppm LTX-diols revealed that their effects on estrous cyclicity were not synergistic. We were unable to detect THF-diols in tissues from rats treated with 10 ppm of the compounds, suggesting that metabolism may be involved. DISCUSSION THF-diols, LTX-diols, and/or their metabolites likely act additively to disrupt endocrine function in male and female rats at concentrations (0.5-1 ppm) that are 200-fold lower than those of classical phytoestrogen endocrine disruptors.