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

Autor: Shaila K. Mani, Barry M. Markaverich, Jan R. Crowley, John Turk, Andrea Reyna, Trellis Thompson, John T. Sharp, Mary Alejandro, Wendy Portillo
Rok vydání: 2007
Předmět:
Male
THF-diols
medicine.medical_specialty
Lordosis
Health
Toxicology and Mutagenesis

Period (gene)
Estrous Cycle
Endocrine Disruptors
Corncob
Zea mays
High-performance liquid chromatography
Gas Chromatography-Mass Spectrometry
Sexual Behavior
Animal

03 medical and health sciences
0302 clinical medicine
Internal medicine
polycyclic compounds
medicine
Animals
Endocrine system
heterocyclic compounds
Furans
Mitogenic activity
030304 developmental biology
No-Observed-Adverse-Effect Level
0303 health sciences
Insect cell
Dose-Response Relationship
Drug

LTX-diols
integumentary system
Chemistry
Research
organic chemicals
Public Health
Environmental and Occupational Health

Biological activity
medicine.disease
Rats
3. Good health
Endocrinology
Linoleic Acids
corncob bedding
Female
hormones
hormone substitutes
and hormone antagonists

Stearic Acids
030217 neurology & neurosurgery
Zdroj: Environmental Health Perspectives
ISSN: 1552-9924
0091-6765
DOI: 10.1289/ehp.9311
Popis: Reports from our laboratory and others have described adverse effects of corncob bedding on reproductive function in rats and mice (Markaverich et al. 2002b; Port and Kaltenbach 1969). For this reason, we recently identified one class of biological agents responsible for blocking male (Mani et al. 2005) and female sexual behavior and cyclicity in adult Holtzman rats (Markaverich et al. 2002a) as an isomeric mixture of 9,12-oxy-10,13-dihydroxyoctadecanoic acid and 10,13-oxy,9,12-dihydroxyoctadecanoic acid (tetrahydrofurandiols; THF-diols; Figure 1). The compounds were synthesized and shown to block male and female sexual behavior and cyclicity at an oral dose of 2 ppm when provided to rats over a 30-day period as a drinking solution. Although Halarnkar et al. (1989, 1992) demonstrated that high (millimolar) concentrations of THF-diols are toxic to insect cells, our studies suggest that at much lower concentrations, they are very active endocrine-disruptive agents in rats that can be purified on the basis of their mitogenic activities in human breast and prostate cancer model systems (Markaverich et al. 2002a). That a similar activity was also described in extracts of fresh corn or cob, and in corn tortillas purchased from a local supermarket further suggested that human exposure was possible (Markaverich et al. 2002a). Therefore, these compounds could represent a significant human health problem if their effects in rats are mirrored in humans (Markaverich et al. 2002b). Figure 1 Structures of THF-diols and LTX-diols. Further characterization of corncob extracts by HPLC led to the isolation, purification, and identification of a second HPLC-peak component with mitogenic activity from ground corncob bedding that also blocked cyclicity in female rats. We identified this activity as 9,10-dihydroxy-12-octadecenoic acid (LTX-diol), a well-known leukotoxin-diol (Markaverich et al. 2005). Like the THF-diols, synthetic preparations of LTX-diols blocked cyclicity in female rats at oral doses of 2 ppm; however, these preparations failed to block male sexual behavior. Thus, sex differences may exist in the response profiles of the THF-diols and LTX-diols in the rat. These earlier studies with synthetic THF-diols or LTX-diols only assessed the effects of a single, higher dose (2 ppm) of these compounds on reproductive function in male (sexual behavior; THF-diols) and female (lordosis and ovarian cyclicity; THF-diols and LTX-diols) rats to confirm the identity of these endocrine-disruptive substances; these higher doses completely ablated the response in these various systems (Markaverich et al. 2002a, 2005). Therefore, we were unable to establish a lowest observed activity level (LOAEL) of the THF-diols and/or LTX-diols responsible for the disruption of endocrine function in these experimental systems. The studies we describe in this article were performed to more precisely define the individual and relative endocrine-disruptive activities of the THF-diols and LTX-diols in female and male rats. We also attempted to determine the levels of the THF-diols present in tissues responsible for their biological activity, and we evaluated the nature of the interaction (additive or synergistic) of THF-diols and LTX-diols when administered to female rats in a combined fashion, as would be the case during exposure to corncob bedding material or other corn preparations.
Databáze: OpenAIRE