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W R Kelce

Publications and source records attributed to W R Kelce.

At least 37 records · Page 2Linked to original sources
PubMed1994

Effects of ethane dimethanesulfonate (EDS) on adult and immature rabbit Leydig cells: comparison with EDS-treated rat Leydig cells.

Ethane-dimethanesulfonate (EDS) has been shown to selectively kill Leydig cells and depress testosterone production in adult rats. A recent study has shown that immature rat Leydig cells are less sensitive to EDS exposure. There is evidence that the rabbit metabolizes EDS to methane sulfonic acid more rapidly than does the rat, reducing exposure to the parent compound. In the study reported here, we examined the effects of EDS on the Leydig cells in both adult and immature rabbits and compared the effects found with those previously reported in the rat. In vivo, EDS exposure demonstrated that Leydig cells from adult rabbits were affected, with both serum and interstitial testosterone production depressed. EDS effects in adult rabbits and rats were compared by exposing explants of testicular parenchyma to EDS in vitro and evaluating testosterone production. With this procedure, the rabbit testis was less sensitive to EDS treatment than the rat, with a 50% reduction rate (EC50) achieved with 2026 microM EDS for the rabbit and with 336 microM EDS for the rat. Perfusion of adult and immature rabbit testis with 430 microM EDS demonstrated the insensitivity of the immature testis to EDS exposure: adult testosterone production was reduced 50% in 3.5 h, whereas no diminution was found in the immature rabbit. EDS exposure of interstitial cell preparations further demonstrated the insensitivity of immature rabbit Leydig cells, with an EC50 of 4397 microM compared to an EC50 of 1137 microM EDS in adult preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Chloroethylmethanesulfonate-induced effects on the epididymis seem unrelated to altered Leydig cell function.

Decades ago it was reported that when male rats were exposed to chloroethylmethanesulfonate (CEMS) for 5 days prior to weekly matings with untreated females, the second mating resulted in reduced litter size. Since fertility was not assessed at earlier time points, it was not possible to determine whether CEMS exerted any effects on sperm in the epididymis. In this study, we used a 4-day exposure and assessed multiple reproductive endpoints on Day 5 to characterize effects of CEMS exposure (6.25-25 mg/kg) on Leydig cells and the epididymis. Exposure to CEMS caused a dose-related decline in serum testosterone (T) levels. This occurred at a dose lower than that required to decrease T production in vitro by testicular parenchyma. The in vitro decline was not attributed to a decrease in maximal hCG-stimulated T production, but to a decrease in unstimulated T production. CEMS was 5-fold less sensitive than ethane dimethanesulfonate (EDS) in reducing maximal hCG-stimulated T production. To control for alterations in the epididymis resulting from decreased serum T alone, T was implanted in CEMS-treated animals to maintain serum T at a concentration similar to that found in normal rats. This exogenous T failed to prevent the CEMS-induced decrease in the weight of the caput/corpus epididymidis but did prevent the CEMS-induced decrease in seminal vesicle weight. Implantation of T failed to prevent the CEMS-induced reduction in sperm reserves in the cauda epididymidis, and it failed to prevent the CEMS-induced alterations in the histology of both the corpus and proximal cauda epididymidis. The height of the epithelium in both of these regions was increased, and clear cells disappeared from the proximal cauda epididymidis. These results demonstrate that CEMS might alter the ability of the Leydig cell to respond to LH stimulation in vivo, and that alterations in the structure and function of the epididymis occur even when the serum concentration of T is maintained.

Alkanesulfonates↗
PubMed1993

Mechanism by which ethane dimethanesulfonate kills adult rat Leydig cells: involvement of intracellular glutathione.

We have previously demonstrated that ethane-1,2-dimethane-sulfonate (EDS) kills adult, but not immature, rat Leydig cells in vivo and in vitro. The mechanism responsible for this selective toxicity is not known. Here we report that the cytotoxic effects of EDS on adult rat Leydig cells were not dependent upon new protein synthesis or cytochrome P450 enzyme activity. To determine whether inhibition of glutathione synthesis protects Leydig cells from the cytotoxic effects of EDS, adult rat Leydig cells were cultured in the presence or absence of 4 mM buthionine sulfoximine (BSO; 2 hr), a specific inhibitor of glutathione synthesis, and subsequently with increasing doses of EDS (3 hr). Following EDS addition, the ability of the cells to produce testosterone in response to LH stimulation, and to synthesize protein ([35S]methionine incorporation) were evaluated. In both cases, Leydig cells cultured in the presence of BSO were far less sensitive than Leydig cells cultured in medium alone (control) to EDS effects on testosterone production (control: EC50 = 60 micrograms EDS/ml; BSO: EC50 > 1500 micrograms EDS/ml) and [35S]methionine incorporation (control: EC50 = 95 micrograms EDS/ml; BSO: EC50 = 1560 micrograms EDS/ml). This protective effect of BSO was abolished by restoring intracellular glutathione levels with glutathione ethyl ester (8 mM; GSHEE). Interestingly, none of these treatments altered the viability (i.e., [35S]methionine incorporation) of immature rat Leydig cells (EC50 = 420 micrograms EDS/ml for control, GSHEE, and BSO groups). Taken together, these data suggest that the mechanism by which EDS kills adult rat Leydig cells may involve Leydig cell glutathione.

Alkylation↗
PubMed1991

Immature rat Leydig cells are intrinsically less sensitive than adult Leydig cells to ethane dimethanesulfonate.

Leydig cells from immature rat testes appear to be insensitive to doses of ethane-1,2-dimethanesulfonate (EDS) which eliminate Leydig cells from adult rat testes. We sought to determine whether this differential response to EDS is intrinsic to the Leydig cell or mediated by other intra- or extratesticular differences between adult and immature rats. To differentiate among these possibilities, Leydig cells were exposed to EDS (1) in vivo, (2) through in vitro testicular perfusion, or (3) in highly purified Leydig cell primary cultures. Four days after ip injections of 85 mg EDS/kg body wt Leydig cells were eliminated from testes of adult, but not immature rats. Total androgen production by testes perfused in vitro with 94 micrograms EDS/ml was dramatically reduced in adult, but not immature rats. Highly purified adult, but not immature, rat Leydig cells were far more sensitive to the effects of EDS on luteinizing hormone-stimulated androgen production (functional effects; apparent EC50 = 94 for adult and 407 micrograms/ml for immature rat Leydig cells) and on [35S]methionine incorporation (cytotoxic effects; apparent EC50 = 140 for adult and 1000 micrograms/ml for immature rat Leydig cells). Finally, the in vitro effects of EDS were both cell type and chemical specific. Since the differential response of adult and immature rat Leydig cells to EDS was manifest in vivo, during in vitro testicular perfusion, and in highly purified Leydig cell primary cultures, we conclude that immature rat Leydig cells are intrinsically less sensitive to the specific cytotoxic effects of EDS than adult rat Leydig cells.

Aging↗
PubMed1991

Male reproductive toxicology.

The objective of this paper is to discuss recent developments in the application of biological markers to animal models of male reproductive toxicology. We have divided this paper into three major sections: First, a discussion of the testing protocols currently under investigation by the National Toxicology Program (NTP) and the EPA's Health Effects Research Laboratory; second, an examination of what we consider to be important and practical biological markers available to investigators to assess the effects of toxicants on the male reproductive system; and third, a discussion of promising new technologies, such as molecular and immunological probes, and in vitro techniques using isolated and cultured cells, which in the future may be exploited for the development of additional biological markers of male reproductive toxicity. Where appropriate we have made specific recommendations for the use of these biological markers in animal protocols and have pointed out those noninvasive markers which have application to screening human males.

Animals↗
PubMed1990

Effects of fetal alcohol exposure on brain 5 alpha-reductase/aromatase activity.

The local formation of the testosterone metabolites 5 alpha-dihydrotestosterone and 17 beta-estradiol within the hypothalamic-preoptic area (HPOA) is essential for the normal sexual differentiation of the male central nervous system (CNS) during a perinatal critical period in the rat. Testosterone, the substrate for these reactions, is derived primarily from synthesis within the fetal testis. Fetal alcohol exposure (FAE) during this critical period profoundly affects fetal testicular steroidogenesis as well as the sexual differentiation of the CNS. The present study was conducted to determine whether FAE directly affects the local metabolism of androgens within the developing CNS or whether reduced androgen substrate, via a testicular lesion, is a more likely explanation for the known effects of FAE on the CNS. The enzymatic activities of 5 alpha-reductase and aromatase were simultaneously quantitated in the newborn rat HPOA following FAE. Neither the enzymatic activity of 5 alpha-reductase, aromatase nor their ratio were significantly influenced (P greater than 0.05) by FAE with respect to controls. FAE apparently does not alter the disposition of the androgens within the newborn rat HPOA. These results support the hypothesis that FAE alters the sexual differentiation of the CNS through inhibition of androgen biosynthesis at the level of the perinatal rat testis.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1990

Influence of rete testis fluid deprivation on the kinetic parameters of goat epididymal 5 alpha-reductase.

A surgical technique to cannulate the rete testis of the goat was utilized to examine the effects of rete testis fluid (RTF) deprivation on the enzymatic activity of epididymal 5 alpha-reductase. Kinetic techniques were used to determine whether the regional enzymatic effect of RTF deprivation is to decrease the apparent number of 5 alpha-reductase active sites or the catalytic activity of each active site within the epididymal epithelium. Paired comparisons of (Vmax)app and (Km)app values between control and RTF-deprived epididymides indicated that RTF deprivation affected the value of (Vmax)app with no apparent change in the values of (Km)app in caput, corpus, and cauda epididymal regions. We conclude that RTF deprivation in the goat epididymis for 7 days results in a decreased number of apparent 5 alpha-reductase active sites within the epididymal epithelium.

Animals↗
PubMed1990

Gonadotoxic effects of 2-hexanone and 1,2-dibromo-3-chloropropane on the enzymatic activity of rat testicular 17 alpha-hydroxylase/C17,20-lyase.

In this study the gonadotoxic effects of 2-hexanone administered as a pretreatment and/or 1,2-dibromo-3-chloropropane administered as a challenge on the activity of several key steroidogenic enzymes in the rat testis were examined. Despite the absence of an effect when either treatment was administered individually, the pretreatment/challenge combination inhibited the steroidogenic capacity of the rat testis. The specific activity of testicular 17 alpha-hydroxylase was significantly reduced (P less than 0.05), with respect to the control, following the pretreatment/challenge combination. There were no significant differences between the control and the individual treatments. The inhibition of 17 alpha-hydroxylase activity occurred in the absence of significant differences in testis weight and testicular protein content. This inhibition of testicular steroidogenic enzyme activity was specific as the activity of another testicular enzyme, namely C17,20-lyase, was not affected by any treatment. The decline in rat testicular 17 alpha-hydroxylase activity 18 h after the 1,2-dibromo-3-chloropropane challenge precedes the reported alterations in the seminiferous epithelium following this same treatment. The results of the present study indicate that the steroidogenic cell of the testis, i.e. the Leydig cell, is a potential site for the primary toxic effects of these agents in the rat testis.

Animals↗
PubMed1990

Differentiation of Leydig cell precursors in vitro: a role for androgen.

An enriched fraction of mesenchymal-like cells was isolated from the testes of 21 day old rats. Testosterone production (ng/10(6) cells.24 hours) by these cells when cultured in vitro was measured by radioimmunoassay of HPLC-purified extracts of culture medium. In the presence of LH + DHT there was a significant increase in testosterone secretion from 22 +/- 10 ng after day 1 of culture to 284 +/- 75 ng on day 3 (P less than 0.01). By contrast, LH or DHT alone were without significant effect. We conclude that LH alone is insufficient but that androgen and LH induce mesenchymal-like Leydig cell precursors from 21 day old rats to produce testosterone.

Animals↗
PubMed1989

Prenatal ethanol exposure alters steroidogenic enzyme activity in newborn rat testes.

We have examined the in utero effects of ethanol exposure on testicular steroidogenesis in newborn male pups. Pregnant Sprague-Dawley rats were fed a liquid ethanol diet (35% ethanol-derived calories), a pair-fed isocaloric liquid diet, or a standard laboratory rat chow and water diet beginning on Day 12 of gestation and continuing through parturition. Although there were no significant differences in the enzymatic activity of 5-ene-3 beta-hydroxysteroid dehydrogenase/isomerase or C17,20-lyase, the enzymatic activity of 17 alpha-hydroxylase was significantly (p less than 0.01) reduced (i.e., approximately 36%) in the ethanol-exposed pups compared to those from the pair-fed and chow treatment groups. This lesion in testicular steroidogenic enzyme activity in newborn male pups exposed to alcohol in utero was transient as 17 alpha-hydroxylase activity from the ethanol-exposed animals returned to control levels by postnatal Day 20 and remained at control levels through adulthood (postnatal Day 60). These data suggest that the suppression of the perinatal testosterone surge in male rats exposed to alcohol in utero and the associated long term demasculinizing effects of prenatal ethanol exposure might be the result of reduced testicular steroidogenic enzyme activity in the perinatal animal.

3-Hydroxysteroid Dehydrogenases↗
PubMed1988

Radiometric quantitation of delta 4-3-ketosteroid-5 alpha-oxidoreductase utilizing high performance liquid chromatography.

A reliable isocratic high performance liquid chromatography (HPLC) procedure has been developed for the separation and subsequent radiometric quantitation of delta 4-3-ketosteroid-5 alpha-oxidoreductase enzyme activity. The specificity of this HPLC procedure has been confirmed through the use of authentic androgen radioisotopes, linearity of detector response, and mass spectral analysis. In conjunction with this we have also developed a simple Sep-Pak sample preparation procedure which allows the uniform complete isolation of these androgens from epididymal tissue homogenates. Utilizing these procedures we have determined the regional distribution of 5 alpha - reductase in the epididymis of the CD-1 mouse. Regional differences in enzyme activity were found between the caput-corpus and cauda regions. Enzyme activity (specific activity) was higher in the caput-corpus region (28.98 pmol 5 alpha - reduced androgens formed/h/mg protein) than the cauda region (6.20 pmol 5 alpha - reduced androgens formed/h/mg protein).

Androstane-3,17-diol↗
PubMed1987

Unique regional distribution of delta 4-3-ketosteroid-5 alpha-oxidoreductase and associated epididymal morphology in the marsupial, Didelphis virginiana.

The epididymal epithelial ultrastructure has been described in the adult male North American opossum, Didelphis virginiana. Morphological results have suggested that absorptive activity is prominent in the proximal epididymal region by virtue of numerous microvilli, an endocytotic complex, dense granules, and multivesicular bodies in the apical cytoplasm. In contrast, the middle and distal epididymal regions exhibit ultrastructural features indicative of protein synthesis such as large invaginated euchromatic nuclei, large nucleoli, and increased amounts of granular endoplasmic reticulum. It is in the middle and distal epididymal regions where sperm head rotation and sperm pairing take place. Epididymal delta 4-3-ketosteroid-5 alpha-oxidoreductase (5 alpha-reductase) activity also has been measured. It has been found that the level of enzyme activity differs significantly (p less than 0.01) between the proximal, middle, and distal epididymal regions. Enzyme-specific activity has been found to be highest in the middle region (47.6 +/- 5.4 picomoles 5 alpha-reduced androgens formed/b/mg protein), lower in the distal region (18.3 +/- 0.7 picomoles 5 alpha-reduced androgens formed/b/mg protein), with little activity (2.4 +/- 1.2 picomoles 5 alpha-reduced androgens formed/h/mg protein) found in the proximal epididymal region. This regional distribution of enzyme activity differs markedly from that reported for eutherian mammals. Both the suggested epididymal protein synthetic and secretory activity and the level of epididymal 5 alpha-reductase activity appear to correlate regionally with the morphological changes that occur in the opossum spermatozoa as they transit the epididymis.

Animals↗
PubMedDate not supplied

Inhibition of testicular steroidogenesis in the neonatal rat following acute ethanol exposure.

We have previously reported detrimental effects of in utero ethanol exposure on testicular steroidogenic enzyme activity in newborn rats. It is now reported that in utero ethanol exposure during Day 12 of gestation through birth has no apparent morphological effect on the testes of Day 1 neonatal rats. It appears that the detrimental effects of ethanol on testicular steroidogenesis can be manifested at the biochemical level in the absence of morphological effects. However, it remained unknown as to whether acute exposure to ethanol would elicit similar biochemical effects as chronic ethanol exposure on testicular steroidogenesis. To test this possibility ethanol was injected at 0, 1, or 2 g/kg intraperitoneally (IP) into rats of various postnatal ages. Plasma ethanol and testosterone levels as well as testicular 17 alpha-hydroxylase and C17,20-lyase activities were measured. The results indicate that acute exposure to ethanol significantly (p less than 0.05) inhibits the catalytic activity of testicular 17 alpha-hydroxylase in the newborn rat testis. This inhibition was specific since the activity of testicular C17,20-lyase was not affected. In conjunction with the reduction in testicular enzyme activity, plasma testosterone levels were reduced to 30% of the control levels in newborn animals receiving ethanol. In older animals, i.e., postnatal Day 20 and 40 rats, plasma testosterone levels were reduced, but not significantly, following ethanol treatment. Furthermore, testicular enzyme activity was not significantly reduced following ethanol treatment in these same older animals. These results suggest that the newborn rat testis is especially sensitive to the effects of ethanol.

Aging↗
PubMedDate not supplied

Latent effects of pesticides and toxic substances on sexual differentiation of rodents.

In humans and rodents, exposure to hormonally active chemicals during sex differentiation can produce morphological pseudohermaphrodism (Schardein, 1993; Gray, 1992). For example, hormonally active drugs like DES (estrogenic), Danazol (androgenic), and progestins cause urogenital malformations in the reproductive tracts of humans and rodents. The current discussion will present new information on the effects of toxic chemicals and pesticides that act on reproductive development via novel mechanisms, including germ cell toxicity, antiandrogenicity, and Ah-receptor binding. Information will be presented that describes how exposure during critical stages of life to synthetic chemicals present in our environment, such as benzidine-based dyes, antiandrogenic fungicides, 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), and PCB congener 169, result in abnormal rodent sex differentiation. In rodents, perinatal exposure to fetal germ cell toxicants reduced the reproductive potential of female, and permanently reduced sperm production in male progeny. Phenotypic sex differentiation, however, was unaffected by these germ cell toxicants. In contrast, antiandrogenic drugs and fungicides induced profound alterations in phenotypic sex differentiation. Effects such as hypospadias, ectopic testes, vaginal pouches, agenesis of the ventral prostate, and nipple retention in male rats were observed commonly. Although these antiandrogens induced no permanent effects in female progeny, another class of chemicals, the Ah-receptor mediated toxicants, did reduce fertility in both male and female rat offspring. Cauda epididymal sperm numbers were reduced permanently in TCDD-exposed male rat and hamster progeny, and female progeny displayed malformations of the external genitalia. Other toxicants produced dramatic alterations of sex differentiation (uterus unicornis, agenesis of the vas and epididymis, and undescended testes), via mechanisms that have not been characterized yet. Since these adult/pubertal alterations resulted from gestational and/or neonatal exposures, future studies should include a comprehensive assessment of reproductive function after perinatal exposure because the developing animal is extremely sensitive to toxicants during sex differentiation, and many of the effects are difficult to detect until late in life.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats.

This study was designed to determine if long-term exposure to high doses of methoxychlor (M) would alter pituitary or testicular endocrine functions in either an estrogenic or antiandrogenic manner. Weanling male Long-Evans hooded rats were dosed daily with M (po) at 0, 200, 300, or 400 mg kg-1 day-1 for 10 months. Methoxychlor treatment delayed puberty by as much as 10 weeks and reduced fertility and copulatory plug formation in a dose-related manner at the initial mating. During mating, M-treated males exhibited shorter latencies to mount and ejaculate versus control males, but the number of intromissions prior to ejaculation was unaffected, indicating that M enhanced the arousal level in the males in an estrogen-dependent manner. Most treated males eventually mated but time-to-pregnancy was lengthened. Very low sperm counts were associated with infertility, while prolonged delays in puberty reduced fecundity. Methoxychlor treatment with 200 to 400 mg kg-1 day-1 failed to mimic the chronic effects of a sustained (8 months) low dose of estradiol-17 beta (3-mm silastic implants) on pituitary or testicular hormone levels. Estradiol administration increased pituitary weight 4-fold, serum levels of luteinizing hormone (LH) were reduced by almost 50%, and serum prolactin was increased 40-fold, while M did not affect any of these measures. These data demonstrate that M affects the CNS, epididymal sperm numbers, and the accessory sex glands and delays mating without significantly affecting the secretion of LH, prolactin, or testosterone. These data indicate that M did not alter pituitary endocrine function in either an estrogenic or antiandrogenic manner. To our knowledge, these data provide the first in vivo example of such a pronounced degree of target tissue selectivity to an environmental endocrine-disrupting chemical.

Animals↗
PubMedDate not supplied

Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat.

In humans and rodents, exposure to antiandrogenic chemicals during sexual differentiation can produce malformations of the reproductive tract. Perinatal administration of 100 or 200 mg vinclozolin (V) kg-1 day-1 during sexual differentiation in rats induces female-like anogenital distance (AGD), retained nipples, cleft phallus with hypospadias, suprainguinal ectopic scrota/testes, a vaginal pouch, epididymal granulomas, and small to absent sex accessory glands in male offspring. Vinclozolin is metabolized to at least two active forms, M1 and M2, that display antiandrogenic activity by binding the androgen receptor (AR). Here, we present information on the reproductive effects of oral treatment with low dosage levels of V during sexual differentiation of the male rat. Vinclozolin was administered to the dam at 0, 3.125, 6.25, 12.5, 25, 50, or 100 mg kg-1 day-1 from gestational day 14 to postnatal day 3 (the period of fetal/neonatal testicular testosterone synthesis and sexual differentiation). At doses of 3.125 mg V kg-1 and above, AGD was significantly reduced in newborn male offspring and the incidence of areolas was increased. These effects were associated with permanent alterations in other androgen-dependent tissues. Ventral prostate weight in one year old male offspring was reduced in all treatment groups (significant at 6.25, 25, 50, and 100 mg kg-1 day-1), and permanent nipples were detected in males at 3.125 (1.4%), 6.25 (3.6%), 12.5 (3.9%), 25 (8.5%), 50 (91%), and 100 (100%) mg V kg-1 day-1. To date, permanent nipples have not been observed in a control male from any study in our laboratory. Vinclozolin treatment at 50 and 100 mg kg-1 day-1 induced reproductive tract malformations and reduced ejaculated sperm numbers and fertility. Even though all of the effects of V likely result from the same initial event (AR binding), the different endpoints displayed a wide variety of dose-response curves and ED50's. The dose-response data for several of the functional endpoints failed to display an obvious threshold. These data demonstrate that V produces subtle alterations in sexual differentiation of the external genitalia, ventral prostate, and nipple tissue in male rat offspring at dosage levels below the previously described no-observed-effect-level (NOEL). These effects occur at a dosage level an order of magnitude below that required to induce malformations and reduce fertility. Hence, multigenerational reproduction studies of antiandrogenic chemicals that were not conducted under the Environmental Protection Agency's new Harmonized Multigenerational Test Guidelines, which include endpoints sensitive to antiandrogens at low dosage levels, could yield a NOEL that is at least an order of magnitude too high.

Administration, Oral↗
PubMedDate not supplied

Peripubertal exposure to the antiandrogenic fungicide, vinclozolin, delays puberty, inhibits the development of androgen-dependent tissues, and alters androgen receptor function in the male rat.

Vinclozolin is a well-characterized antiandrogenic fungicide. It produces adverse effects when administered during sexual differentiation, and it alters reproductive function in adult male rats by acting as an androgen-antagonist. Two active metabolites of vinclozolin, M1 and M2, compete with natural androgens for the rat and human androgen receptors (ARs), an effect that blocks androgen-induced gene expression in vivo and in vitro. In addition to their effects during perinatal life, androgens play a key role in pubertal maturation in young males. In this regard, the present study was designed to examine the effects of peripubertal oral administration of vinclozolin (0, 10, 30, or 100 mg kg-1 day-1) on morphological landmarks of puberty, hormone levels, and sex accessory gland development in male rats. In addition, as binding of the M1 and M2 to AR alter the subcellular distribution of AR by inhibiting AR-DNA binding, we examined the effects of vinclozolin on AR distribution in the target cells after in vivo treatment. We also examined serum levels of vinclozolin, M1, and M2 in the treated males so that these could be related to the effects on the reproductive tract and AR distribution. Vinclozolin treatment delayed pubertal maturation (at 30 and 100 mg kg-1 day-1) and retarded sex accessory gland and epididymal growth. Serum luteinizing hormone (LH; significant at all dosage levels) and testosterone and 5 alpha-androstane, 3 alpha, 17 beta-diol (at 100 mg kg-1 day-1) levels were increased. Testis size and sperm production, however, were unaffected. It was apparent that these effects were concurrent with subtle alterations in the subcellular distribution of AR. In control animals, most AR were in the high salt cell fraction, apparently bound to the natural ligand and DNA. Vinclozolin treatment reduced the amount of AR in the high salt (bound to DNA) fraction and it increased AR levels in the low salt (inactive, not bound to DNA) fraction. M1 and M2 were found in the serum of animals from the two highest dosage groups, but they were present at levels well below their K1 values. In summary, these results suggest that when the vinclozolin metabolites occupy a small percentage of AR in the cell, this prevents maximal AR-DNA binding and alters in vivo androgen-dependent gene expression and protein synthesis, which in turn results in obvious alterations of morphological development and serum hormone levels. It is noteworthy that similar exposures during prenatal life result in a high incidence of malformations in male rats.

Administration, Oral↗