Disruption of male sexual behavior in rats by tetrahydrofurandiols (THF-diols)
Introduction
Environmentally-derived phytoestrogens and mycotoxins are endocrine disruptors that profoundly affect reproduction in mammals [1], [2]. These agents mimic or antagonize the effects of endogenous steroid hormones and disrupt the synthesis and metabolism of endogenous hormones or hormone receptors, resulting in disruption of a wide variety of endocrine and reproductive functions. Phytoestrogens modulate estrogen receptor α (ERα) mediated pathways regulating cellular differentiation and reproduction in reproductive tissues [3]. Consumption of soy-supplemented diets stimulates mild vaginal cornification in postmenopausal women [4]. These data suggest that phytoestrogens with impeded activity competitively block the action of physiological estrogens and this may be one way these compounds hypothetically reduce breast cancer incidence in humans. Alternatively, it is also clear that sustained exposure to impeded estrogens or antiestrogens causes mammary cancer in rats [5]. Thus, the pathways dictating biological response to phytoestrogens in females are complex. Several studies have also documented the effects of endocrine disruptors in males. For example, the estrogenic potential of pesticides like DDT was reported to be responsible for low sperm counts and loss of libido in humans [6] and laboratory animals [7]. Studies have also reported an increase in prevalence of cryptorchidism and hypospadias [8] as well as an increase in testicular cancer in men [9]. While the causes for the increase in incidence are unknown, the mitogenic potential of endocrine disruptors in the environment cannot be ignored.
We recently reported the presence of a chemical agent in corncob animal bedding, a crude preparation of which not only stimulated proliferation of human breast and prostate cancer cells in vitro but also disrupted male and female reproductive behavior and estrous cyclicity in rats [10]. We further demonstrated that the mitogenic activity resided in an isomeric mixture of linoleic acid derivatives with a tetrahydrofuran ring and two hydroxyl groups (THF-diols) that include 9, (12)-oxy-10, 13-dihydroxtstearic acid and 10, (13)-oxy-9, 12-dihydroxystearic acid [11]. These compounds apparently do not interact via classical ER pathways. Although, classical [3H]estradiol exchange assays do not discriminate between ligand binding to ERα or ERβ in rat uterine nuclear fractions, the failure of the THF-diols to compete for [3H]estradiol binding in these assays, suggests they do not bind to either form of this protein. In animal studies, the THF-diols disrupt estrous cyclicity in rats at doses ∼200 times lower than classical phytoestrogens suggesting they are very active endocrine disrupters [11]. The present studies describe the effects of equivalent concentrations of THF-diols on several parameters of male sexual behavior in rats.
Section snippets
Animals and treatment
Eight adult Sprague Dawley male rats weighing 180–200 g and eight ovariectomized females (160–180 g) were commercially obtained the supplier (Harlan, Houston, TX). The animals were housed on suspended wire cages and maintained in compliance with federal guidelines for animal care on a 12 h:12 h reversed light cycle with lights off at 12:00 h. The institutional animal care and use committee at Baylor College of Medicine approved all procedures. Food and water were provided ad libitum. All compounds
THF-diol isomers affect male sexual behavior
THF-diols administered in drinking water significantly affected several parameters of male sexual behavior. The frequency of mounts (MF), intromission (IF) and grooming (GF) were significantly reduced in animals (P < 0.001) that received THF-diol isomers compared to the control and vehicle-treated groups (Table 1). While the latencies to mount (ML), intromit (IL) and ejaculate (EL) were enhanced in THF-diol-treated animals, they were not statistically significant (P > 0.05) due to the variation in
Discussion
The present results confirm and extend our previous observations on the effects of crude corn bedding extracts on male sexual behavior in rats [10]. The purified active components from the extract was identified as an isomeric mixture of linoleic acid derivatives containing a tetrahydrofuran ring and two hydroxyl groups (THF-diols) that include 9, (12)-oxy-10, 13-dihydroxtstearic acid and 10, (13)-oxy-9, 12-dihydroxystearic acid (11). A mixture of authentic THF-diols has biological functions
Acknowledgements
This work was supported by grants from the National Institute of Environmental Health Sciences (ES09964), the American Institute for Cancer Research (98A077), the National Institute of Mental Health (MH 57442, MH 63954), the Office of Research on Woman's Health, the National Cancer Institute (CA-35480) and grant number P41-RR-00954 from the National Council of Research Resources of the NIH.
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