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

Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats-3

<p><b>Copyright information:</b></p><p>Taken from "Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats"</p><p></p><p>Environmental Health Perspectives 2007;115(5):702-708.</p><p>Published online 29 Jan 2007</p><p>PMCID:PMC1868002.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI</p

Effects of THF-diols on the estrous cycle of adult female Holtzman rats treated with vehicle (controls) or various doses (0

<p><b>Copyright information:</b></p><p>Taken from "Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats"</p><p></p><p>Environmental Health Perspectives 2007;115(5):702-708.</p><p>Published online 29 Jan 2007</p><p>PMCID:PMC1868002.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI</p>2, 0.5, or 1 ppm) of approximately 1:1 mixture of THF-diol isomers. See “Materials and Methods” for details. Of the vehicle controls, 100% (8/8) displayed normal (5–7 day) cycles, whereas cyclicity was suppressed in the 0.2-ppm (75% normal cycles; 6/8 rats), 0.5-ppm (87.5% normal cycles; 7/8), and 1.0-ppm (22% normal cycles; 2/9 rats) treatment groups. Four rats in the 1.0-ppm group displayed a single estrus smear during the 30-day period

Effects of THF-diols on the estrous cycle of adult female Holtzman rats treated with vehicle (controls) or with LTX-diols (0

<p><b>Copyright information:</b></p><p>Taken from "Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats"</p><p></p><p>Environmental Health Perspectives 2007;115(5):702-708.</p><p>Published online 29 Jan 2007</p><p>PMCID:PMC1868002.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI</p>2, 0.5, or 1.0 ppm; dose–response study) or LTX-diols plus THF-diols (0.05 ppm each; combination study) as described in “Materials and Methods.” The data for the dose–response study are also summarized in . Data for the combination study are summarized in

Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats-8

<p><b>Copyright information:</b></p><p>Taken from "Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats"</p><p></p><p>Environmental Health Perspectives 2007;115(5):702-708.</p><p>Published online 29 Jan 2007</p><p>PMCID:PMC1868002.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI</p

Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats-4

<p><b>Copyright information:</b></p><p>Taken from "Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats"</p><p></p><p>Environmental Health Perspectives 2007;115(5):702-708.</p><p>Published online 29 Jan 2007</p><p>PMCID:PMC1868002.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI</p

Effects of THF-diol on mounting frequency () and mounting latency () in male rats given vehicle (controls), or 0

<p><b>Copyright information:</b></p><p>Taken from "Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats"</p><p></p><p>Environmental Health Perspectives 2007;115(5):702-708.</p><p>Published online 29 Jan 2007</p><p>PMCID:PMC1868002.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI</p>2 or 1.0 ppm THF-diols for 14 days. Results are expressed as mean ± SE for triplicate determinations from 6 rats for each dose level; data were analyzed statistically as described in “Materials and Methods.” No significant treatment effects were observed, although the decrease in mounting frequency approached significance in both THF-diol treatment groups

Number of female rats displaying normal (5–7 day) estrous cycles after treatment with vehicle or 0

<p><b>Copyright information:</b></p><p>Taken from "Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats"</p><p></p><p>Environmental Health Perspectives 2007;115(5):702-708.</p><p>Published online 29 Jan 2007</p><p>PMCID:PMC1868002.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI</p>2, 0.5, or 1 ppm THF-diol. See “Materials and Methods” for details