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PubMed2003

Spermatogenetic disorders in adult rats exposed to tributyltin chloride during puberty.

Adverse effects of tributyltin (TBT) chloride were investigated on the reproductive system in male adult rats as exposed during puberty. Fifty Sprague-Dawley rats at the age of 35 days were assigned to five different groups: negative control receiving vehicle, methyltestosterone (10 mg/kg B.W.), and TBT chloride treatments (5, 10, and 20 mg/kg B.W.). Animals were treated by oral gavage for ten consecutive days and sacrificed at 5 weeks after final treatment. The treatment of TBT chloride at the high dose of 20 mg/kg B.W. significantly decreased homogenization-resistant testicular sperm counts (p<0.05). The TBT chloride treatment at the doses of 10 and 20 mg/kg B.W. also significantly decreased caudal epididymal sperm counts (p<0.01). Some of motion kinematic parameters (motility, mean angular displacement, lateral head displacement, and dance) of sperms retrieved from vasa deference were significantly decreased in rats treated with the TBT chloride at the dose of 20 mg/kg B.W. (p<0.05). These results provide a further evidence that an exposure to TBT chloride during pubertal period in male rats produces spermatogenic disorders characterized by decreasing testicular and epididymal sperm counts and some motion parameters of sperms in the vasa deference.

Animals↗
PubMedDate not supplied

Low plasma testosterone in varicocele patients with impotence and male infertility.

To study the affect of bilateral varicocele (grade 3) on impotence and male infertility patients, 29 patients were selected from an outpatient clinic during 15 May 1998 to 15 August 1999 (the mean age was 33.9 +/- 6.3), 15 patients complaining of erectile dysfunction and 14 patients complaining of male infertility. The mean duration of impotence was 3 +/- 2.3 years and for male infertility was 6 +/- 2.5. All organic and psychogenic causes related to impotence and male infertility except bilateral varicocele (grade 3) and low plasma testosterone were excluded by clinical and laboratory investigations. Twenty males with normal erection and fertility were included as controls. Detailed medical history and complete physical examination included measurement of testicular size by orchiometer; semen and hormonal parameters were measured for all patients and control. In impotent patients left and right testicular volume was significantly decreased (p < .05), while in male infertility patients left and right testicular volume was highly significantly and, significantly decreased (p < .005, p < .05) compared to controls. In male infertility patients, left testicular volume was highly significantly decreased compared to impotent patients (p < .005). The sperm count and semen volume in impotent patients was significantly decreased (p < .05, p < .01), but no significant differences were found in sperm motility and abnormal forms, while in male infertility the sperm count was highly significantly decreased (p < .005), the sperm motility was significantly decreased (p < .05), the abnormal form was significantly increased (p) < .05), but in the semen volume there was no significant difference compared to controls. In impotent patients the sperm count was significantly increased and abnormal form was significantly decreased compared to male infertility (p < .05). The mean serum testosterone was significantly decreased in impotent patients (p < .01), and highly significantly decreased in male infertility (p < .005) compared to controls. The mean serum FSH was significantly increased in male infertility (p < .05) and nonsignificant in impotent patients compared to controls. The mean serum LH and prolactin levels were nonsignificant in both impotent and male infertility patients compared to controls, but LH was significantly increased in impotence compared to male infertility patients (p < .025). Therefore, bilateral varicocele (grade 3) is associated with significant reduction in testicular function with significant increase in serum levels of FSH and LH, which may cause erectile dysfunction and male infertility.

Adult↗
PubMed1979

Testicular function among carbaryl-exposed exployees.

A cohort of 101 male carbaryl production workers with at least 1 yr experience in the carbaryl area was selected from employment records. Of these individuals, 47 provided satifactory semen samples for analysis; 36 of the 47 provided blood for hormone assay. There were no major age or employment-status differences between those who agreed to participate and those who did not. In the absence of sufficiently detailed industrial hygiene exposure data, a subjective exposure classification was developed. No apparent relationships were found between sperm count and exposure category or years worked in classifications based on carbaryl exposure. Also, no relationship was found between fathering children and exposure to carbaryl. When the sperm-count distribution of the carbaryl-exposed workers was compared with a distribution of sperm counts representing a nonexposed (control) population, no overall differences were observed that could be related to carbaryl exposure. There was a small excess in the number of sperm counts less than 20 million per milliliter among the carbaryl-exposed men, but the excess was not significant at alpha = 0.05.

Adult↗
PubMed2001

The postwash total progressively motile sperm cell count is a reliable predictor of total fertilization failure during in vitro fertilization treatment.

OBJECTIVE: To predict the chance of total fertilization failure (TFF) before the day of ovum pickup with known semen and female variables. DESIGN: A statistical model was constructed to predict TFF by retrospective analysis (2,366 couples) and subsequently tested on a new IVF population (917 couples). SETTING: Academic tertiary referral center. PATIENT(S): Three thousand three hundred eighty-three couples who underwent an IVF-ET treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The ability to predict the probability of TFF in IVF. RESULT(S): Two variables-postwash total progressively motile sperm cell count (postwash TPMC) and number of follicles-were found to be significant. Taking a probability of 25% as an acceptable risk of TFF, we calculated that a postwash TPMC of <1.1 x 10(6) cells results in a risk of TFF of >25%. Low responders (<4 follicles) needed a postwash TPMC of >2.2 x 10(6) cells to reduce the risk of TFF to <25%. High responders (>15 follicles) needed only 0.35 x 10(6) postwash progressively motile spermatozoa. CONCLUSION(S): When postwash TPMC and number of follicles are known and an unacceptable TFF outcome is expected, one can propose an ICSI procedure a few days before the day of ovum pickup.

Female↗
PubMed1997

Is semen quality related to the year of birth among Danish infertility clients?

BACKGROUND: There is circumstantial evidence that human sperm count may have declined during past decades. The purpose of this study was to identify the association between semen quality and year of birth. METHODS: The study comprised 8608 men consulting four Danish medical centres from 1968 to 1992 because of infertility. Data on semen quality and urogenital disorders were obtained from medical records while lifestyle data were collected from a subset of the population by a postal questionnaire (response 80%). Semen characteristics were analysed as a linear function of year of birth, centre, season and calendar year at time of semen examination, sexual abstinence and lifestyle factors. Effects of age were accounted for by restriction and stratified analysis. RESULTS: The sperm count declined with increasing year of birth at two of the four centres, but this association disappeared when confounders were adjusted for. Within the subset of men born 1950-1970 we revealed a decrease in the average sperm count by 1.9 mill/ml (95% confidence interval [CI]: 1.45, 2.27) per one advancing year of birth. This finding was consistent across centres even after adjustment for effects of covariates. The proportion of morphologically normal sperm cells changed in parallel with the sperm count, while semen volume did not decline in any time periods. CONCLUSIONS: We found a birth cohort effect on sperm count and morphology among Danish infertile men born after 1950 but not in men born in the first part of the century. The findings are compatible with an environmental impact during prenatal life but the evidence is far from unequivocal.

Adult↗
PubMed1984

Ethylene oxide: an overview of toxicologic and epidemiologic research.

Ethylene oxide (EtO) is a reactive epoxide and potent biocide. It is used widely in gas sterilization of hospital equipment. An estimated 75,000 health care workers in the United States have potential exposure. EtO binds covalently to deoxyribonucleic acid (DNA) and has been shown in 13 species to cause point mutations. Apparently, as a consequence of its alkylating ability, EtO exposure can result in chromosomal damage. In monkeys EtO exposure produces increased frequencies of sister chromatid exchanges (SCEs) and chromosomal aberrations. In man, five cytogenetic studies have shown dose-related increased frequencies of either SCE or chromosomal aberrations; in one study SCEs developed after regular exposures lasting less than five minutes per day. EtO is a reproductive toxin. In adult male rats, exposure produces decreased fertility, increased fetal deaths, and heritable chromosomal translocations. In pregnant female rats and rabbits, exposure causes increased fetal losses, and in one study in pregnant mice exposure was associated with increased numbers of malformed fetuses. In male monkeys EtO causes dose-related reductions in sperm count and sperm motility. In pregnant women, one study suggests that brief occupational exposure twice daily in concentrations of 20 ppm or above was associated with increased spontaneous abortions. EtO is carcinogenic to animals. In rats it causes dose-related increases in mononuclear cell leukemias, peritoneal mesotheliomas, and cerebral gliomas. In man, exposure has been associated in two epidemiologic studies with increased leukemias: 3 leukemias observed versus 0.2 expected in one study, and 2 observed versus 0.14 expected in the other; two additional small studies of limited power found no excess leukemias. Quantitative risk assessment indicates that from 634 to 1,093 excess deaths from cancer will occur per 10,000 workers exposed to EtO at 50 ppm over a working lifetime, and that 12 to 23 excess cancer deaths will occur per 10,000 workers exposed at 1 ppm. The National Institute for Occupational Safety and Health (NIOSH) recommends that EtO be regarded as a potential human carcinogen. NIOSH has recommended that eight-hour time-weighted average exposure to EtO be less than 0.1 ppm and that short-term peak exposure not exceed 5 ppm for more than ten minutes per working day.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Diagnostic value of sperm function tests and routine semen analyses in fertile and infertile men.

The results of routine semen analyses, the zona-free hamster oocyte penetration test, the hypoosmotic swelling test, and semen adenosine triphosphate levels were studied in 66 fertile and 130 infertile men. Multivariate discriminant analysis demonstrated that routine semen parameters including semen volume, sperm count, percent sperm motility, and percent normal spermatozoa in combination could predict the fertility of these patients with 70.4% accuracy. Of the three sperm function tests evaluated, the zona-free hamster oocyte penetration test and the hypoosmotic swelling test were selected by the multivariate discriminant analysis as variables capable of providing significant information on the fertility status of the patients. However, the addition of the results of these two tests to the routine semen analysis did not significantly improve the predictability of fertility. The overall correct prediction rate was 77.6% after incorporation of the results of these two sperm function tests. In this group of subjects, the presently available sperm function tests did not predict the fertility status of a patient with a high degree of accuracy.

Diagnostic Tests, Routine↗
PubMed2002

Effect on growth and reproduction of hormone immersed and masculinized fighting fish Betta splendens.

To produce all-male progenies in the fighting fish, Betta splendens, six groups of fry were subjected to discrete immersion treatment at different 17alpha-methyltestosterone (MT) doses (viz. 100, 200, 500, 700, 900, and 1,000 microg/l) for a constant duration (3 hr/day) and frequency (second, fifth, and eighth day after hatching). The treatment at 900 microg/l led to 98% masculinization and 71% survival at sexual maturity. Treated groups, which showed significant deviation from the 1:1 sex ratio, were classified into two different series: S1 and S2. The groups that showed nearly cent-percent masculinization were classified as S1, and the other groups were classified as S2. The S1 males showed remarkably slower growth and attained 3.5 cm total length compared to 6.0 cm attained by a normal male. The S2 males attained 5.4 cm total length. Apart from these morphological defects, both S1 and S2 males suffered functional (decreased sperm count and sperm motility) and behavioral defects (incomplete embracing during mating) in their reproductive ability, leading to approximately 50% and 30% reduction in fecundity per mating, respectively. The cumulative fecundity loss suffered by the S1 male during its active reproductive phase is discussed. When normal and sex-reversed males were presented, a female preferred the former. Progeny testing of the sex-reversed males showed the occurrence of 12.75% males, indicating the possible role of autosomal genes in the sex determination mechanism of this species. Discrete immersion treatment at optimal/super-optimal doses ensured not only a higher percentage of masculinization, but also a higher frequency of homogametic males (XX).

Animals↗
PubMed1999

Normal reproductive organ development in Wistar rats exposed to bisphenol A in the drinking water.

Bisphenol A (BPA) is a chemical used primarily as a monomer in the manufacture of numerous chemical products, such as epoxy resins and polycarbonate. The objective of this study was to evaluate potential effects of BPA on sexual development of male rats and was designed to clarify low-dose observations reported as preliminary results by Sharpe et al. (1996). The protocol for the present study followed the same treatment schedule as reported by Sharpe et al. (1995, 1996), but included more treatment groups, a greater number of animals per group, and a more comprehensive number of reproductive endpoints. Groups of 28 female Han-Wistar albino rats were exposed to drinking water that contained 0, 0.01, 0.1, 1.0, or 10 ppm BPA or 0.1 ppm diethylstilbestrol (DES), 7 days per week, for a total of 10 weeks. Treatment of the females began at 10 weeks of age and continued throughout a 2-week premating period, 2 weeks of mating (to untreated males), 21-22 days of gestation, and 22 days of lactation. Offspring weanling males were given untreated drinking water and maintained until 90 days of age when evaluations were made of various reproductive organs. Consistent with Sharpe et al. (1996) the female offspring were not evaluated. No treatment-related effects on growth or reproductive endpoints were observed in adult females exposed to any concentration of BPA. Similarly, no treatment-related effects were observed on the growth, survival, or reproductive parameters (including testes, prostate and preputial gland weights, sperm count, daily sperm production, or testes histopathology) of male offspring from dams exposed to BPA during gestation and lactation. DES administered in the drinking water at 0. 1 ppm resulted in decreased body weight, body weight change, and food consumption in adult females. In addition, an increase in the duration of gestation and a decrease in the number of pups delivered and number of live pups were also observed in animals exposed to DES. In conclusion, these results do not confirm the previous findings of Sharpe et al. (1996) and show that low doses of BPA had no effects on male sexual development in the rat.

Air Pollutants, Occupational↗
PubMed1995

Effect of hypoxia by intermittent altitude exposure on semen characteristics and testicular morphology of male rhesus monkeys.

Semen characteristics and testicular morphology of rhesus monkeys were studied on exposure to a simulated high altitude of 4411 m for 21 days. There was a partially reversible decrease in the semen volume, sperm count and sperm motility, as well as an elevation of pH and fructose concentration. These changes were associated with degeneration of the germinal epithelium and spermatogenic arrest at the end of third week of exposure which had not recovered even 3 weeks after the exposure.

Altitude Sickness↗
PubMed1992

Adverse male reproductive effects following subchronic exposure of rats to sodium dichloroacetate.

Dichloroacetate (DCA) activates the pyruvate dehydrogenase complex enhancing carbohydrate and lactate utilization in animals. As a result it is used clinically in the treatment of acute lactic acidosis and has therapeutic potential in the treatment of stroke. Adverse effects of chronic DCA treatment include polyneuropathy and testicular degeneration. Since DCA is a principal product of the aqueous chlorination of fulvic acids concern has arisen regarding the agent's impact on environmental health. We treated male Long-Evans rats with 0, 31.25, 62.5, or 125 mg DCA/kg/day by oral gavage for 10 weeks. Compared to controls, preputial gland and epididymis weights were reduced at 31.25 mg/kg, body and liver weights at 62.5 mg/kg, and accessory organ weights at 125 mg/kg. Epididymal sperm counts were reduced and sperm morphology was impacted at the 62.5 and 125 mg/kg doses levels. Histologic examination of the testis and epididymis revealed inhibited spermiation in testes at the 125 mg/kg dose level. Computer-assisted sperm motion analysis revealed reductions in percentage motile sperm, curvilinear and straight-line velocity, linearity, and amplitude of lateral head displacement at both the 62.5 and the 125 mg/kg dose levels. In the assessment of fertility after an overnight mating, the number of viable implants on Day 14 of gestation was decreased only in the highest dose group. These studies demonstrate adverse effects of NaDCA treatment on the rat male reproductive system, primarily on the accessory organs and sperm within them at lower doses (31.25 and 62.5 mg/kg), and on the testis at the highest dose (125 mg/kg).

Animals↗
PubMed1992

Two-generation reproduction study of hydrotreated shale oil vapors.

Two generations of Sprague-Dawley rats were each exposed to vapors generated by countercurrent distillation (50 degrees C) at 0, 0.5, 2.5, and 5.0 mg/liter, for 6 hr/day, 5 days/week, for 124-126 days prior to mating. After mating, exposure was continuous except for the last day of gestation through lactation for F0 dams, and the last day of gestation through Day 6 of lactation for F1 dams. F1 pups were not exposed during lactation; F2 pups were exposed via nursing only. Body weights were recorded weekly before mating; organ and body weights were recorded on Days 1, 13, and 30 of gestation and on Days 1, 4, and 21 of lactation. Histopathology, reproductive performance, and certain sperm parameters were evaluated. The test material significantly (p less than 0.05) depressed body weights of F0 males and brain and lung weights of F1 weanling males at 5.0 mg/liter. Testicular weights of F1 weanling males were depressed at the 0.5 and 5.0 mg/liter concentrations. While a dose-related decrease in sperm count and sperm ATP levels and an increase in ATP/sperm ratios were observed in F0 males at 2.5 and 5.0 mg/liter, there was no adverse effect on overall reproductive performance.

Animals↗
PubMed1992

Endpoints of spermatotoxicity in the rat after short duration exposures to fourteen reproductive toxicants.

Multiple endpoints of spermatotoxicity in short duration tests (1-5 days exposure; 2.5-week assay interval) were investigated in a number of chemicals reported to produce minimal to severe reproductive effects when administered subchronically. Six of these chemicals (boric acid, dinoseb, 2,5-hexanedione, methoxychlor, metronidazole, ornidazole) produced substantial spermatotoxicity after 1 to 5 doses. Spermatotoxic effects of chlordimeform were equivocal while p,p'-DDT, n-hexane, and sodium chlorite were judged negative. Four chemicals with known acute effects (benomyl, busulfan, ethylene glycol monomethyl ether, nitrobenzene) elicited expected histopathologic responses after a single dose. Testicular histology, testicular sperm head counts, cauda sperm counts, sperm morphology, and sperm velocity proved to be the most toxicologically sensitive endpoints in one or more of the studies, but histopathology of the testis and epididymis was the most consistent indicator of reproductive damage. The percentage of motile sperm and sperm concentration in the epididymal fluid were the least sensitive measurements. The data suggested that most chemicals with the potential to produce moderate to severe sperm damage are detectable with a short duration test. Complementary multiple endpoints enhanced the interpretation of results, often identified cellular targets, and provided insight on possible mechanisms. Specific responses were often similar to specific effects reported for subchronic exposures. A short duration test could be of value as a screen in structure-activity studies or to set priorities for chemicals requiring further evaluation. As a supplement to breeding studies, the data generated in the short test could also be used to enhance the design and interpretation of the longer tests.

Animals↗
PubMed2004

Transfer and uterine factors are the major recipient-related determinants of success with donor eggs.

OBJECTIVE: To define the recipient-related determinants of outcome with donor eggs. DESIGN: Case-control study. SETTING: Community hospital-based assisted reproductive technology (ART) program. PATIENT(S): One hundred thirty-four embryo transfers (ETs) in which two recipients were matched to one donor. INTERVENTION(S): Controlled ovarian hyperstimulation (COH) and ovum retrieval in donors; IVF and ET to recipients. MAIN OUTCOME MEASURE(S): Recipients' age, body mass index (BMI), medical conditions, endometriosis, gravidity, uterine pathology, endometrial thickness, egg number, total motile sperm count, intracytoplasmic sperm injection (ICSI), zygote number, fertilization rate, embryos per ET, embryos frozen, embryo quality, difficulty with transfer, and ongoing pregnancies per ET. RESULT(S): Forty-one recipient pairs had discordant outcomes. Pregnant patients had a lower frequency (9.7% vs. 31.7%, P=.04) and lesser severity of uterine pathology. Endometrium <8 mm was found solely in failed cycles. Pregnant women had fewer moderate or difficult ETs (9.7% vs. 31.7%, P=.04) and more good embryos (1.8 vs. 1.3, P=.03) than the nonpregnant group. CONCLUSION(S): Analysis of recipient pairs with discordant outcomes identifies the recipient-related predictors of success by keeping oocyte quality and the laboratory component constant. Uterine pathology, thin endometrium, transfer difficulty, and number of high-grade embryos are the principal recipient-related determinants of outcome with donor eggs.

Adult↗
PubMed2004

Reproductive toxicity assessment of chronic dietary exposure to soy isoflavones in male rats.

Epidemiologic and experimental data suggest that consumption of diets that are rich in isoflavones may decrease cancer risk in the breast, prostate, and other tissues. Isoflavones such as genistein and daidzein are structurally similar to endogenous estrogens, and demonstrate both estrogenic and weak anti-estrogenic activities; these activities may underlie the impaired fertility and reproductive tract disorders reported in animals exposed to high doses of isoflavones. To identify possible effects of isoflavones on male fertility, we evaluated reproductive parameters in Wistar-Unilever rats receiving dietary exposure to PTI G-2535, a characterized mixture of soy-derived isoflavones containing 45% genistein, 23% daidzein, and 4% glycitein. Beginning at 10 weeks of age, rats received chronic dietary exposure to the soy isoflavone mixture (200 or 2000 mg/kg diet) for a minimum of 12 months. Controls received unsupplemented chow diet only for the same period. Dietary exposure to isoflavones induced no gross toxicity or alterations in body weight gain. Absolute and relative weights of the testis and epididymis in groups receiving high or low doses of isoflavones were comparable to those of controls, and histopathologic evaluations demonstrated that testicular morphology was similar in all study groups. Isoflavone exposure had no significant effects on spermatid count, sperm production, or sperm morphology in any group. These data suggest that the reproductive system of adult male rats is relatively insensitive to isoflavone toxicity at dose levels that demonstrate significant activity in cancer chemoprevention, and that male reproductive function is unlikely to be affected by long-term administration of isoflavones for cancer prevention or other purposes. The results of this study conducted in adult male rats differ from the significant alterations in reproductive parameters that have been reported in female rats receiving prenatal or juvenile exposure to isoflavones.

Animals↗
PubMed2004

The effects of tetrathiomolybdate (TTM, NSC-714598) and copper supplementation on fertility and early embryonic development in rats.

Based on its ability to chelate copper, TTM is being studied as an antiangiogenic agent for cancer therapy. The purpose of this study was to evaluate the toxicity of TTM and the protection of copper supplementation on the reproductive capability of male and female CD rats. Doses of 0, 1, 4, and 12 mg/kg/day with copper supplementation (110 mg/kg of diet) were given by gavage. There were no effects on the estrous cycle or reproductive indices, or maternal toxicity in any female dose group. Male rats given 12 mg/kg/day showed significant decreases in body weight gains and food consumption, and anemia. Serum ceruloplasmin levels were dose-dependently decreased in all male dose groups. Reduced epididymal weights, sperm counts, and sperm motility, sperm morphologic abnormalities and histopathologic changes in testis and epididymis occurred only at 12 mg/kg/day. Dietary copper supplementation prevented the adverse sperm effects produced by 12 mg/kg/day of TTM.

Adenosine Triphosphatases↗
PubMedDate not supplied

Effect of dietary plant and animal protein intake on sperm quality in monkeys.

This study was conducted to evaluate the influence of animal and plant protein diets on sperm quality indices over 120 days, using the vervet monkey (Cercopithecus aethiops), as a model. These experiments were divided into a 60-day period of high-protein consumption (+/-17% crude protein), followed by a 60-day term of sustainable protein intake (+/-9% crude protein). All the diets were designed to be similar, except for the source of dietary protein that the animals consumed. High-protein diets containing milk solids or maize + legumes had no significant effect on sperm quality parameters over the first 60 days. During the next 60 days of the investigation, sustainable plant and animal protein diets had differential effects on a number of sperm quality indices. When compared to the plant-based diet, the monkeys that were given the animal protein diet containing milk solids had lower sperm counts (p < .04), reduced sperm motility (p = .04), higher sperm midpiece abnormalities (p < .05), and a trend (p = .10) towards increased sperm head defects. These findings shed some light on the impact of variable dietary proteins on sperm quality, but should be followed by longer-term investigations around this important reproductive health issue.

Animals↗
PubMedDate not supplied

Dietary administration of colesevelam hydrochloride does not affect fertility or reproductive performance in rats.

Colesevelam hydrochloride (HCl) (WelChol; Sankyo Pharma) is a novel, highly potent, bile acid-binding polymer used for the treatment of hypercholesterolemia. The primary aim of this study was to determine the effects of dietarily administered colesevelam HCl on fertility and reproductive performance parameters. To assess these effects, sexually mature Sprague-Dawley rats were randomized to one of five treatment groups: feed alone, feed plus control article (SigmaCell), or feed plus colesevelam HCl 200, 1000, or 2000 mg/kg/day. Male and female rats were administered the appropriate group agent for 28 and 15 days, respectively, and were subsequently paired together for cohabitation and mating. Females continued to receive the test agent in their dietary formulation through presumed gestation day (GD) 7. Presumed pregnant females underwent cesarean section on GD 20. Food consumption rate, body weight, gross necropsy, and standard preclinical tests for reproduction and fertility were performed for each test animal. No statistically significant differences were found between control and drug-treated groups for any tested endpoints of reproduction. All animals placed in cohabitation successfully mated. Uterine and litter end points were unaffected by dosages of colesevelam HCl as high as 2000 mg/kg/day. There were no significant differences between treatment group litter averages in the number of corpora lutea, implantation sites, litter size, live fetuses, body weights, early/late resorptions, and the number of dams with viable fetuses. In addition, no external alterations of fetal morphology were attributable to treatment with colesevelam HCl when administered up to the embryo implantation stage. In male animals, no significant differences were found between the colesevelam HCl and control study groups in the average caudal epididymal sperm count or sperm concentration, total number of motile and nonmotile sperm, and the total percentage of motile sperm. Based on these data, colesevelam HCl does not have any significant adverse reproductive or fertility effects in rats, even when administered at doses approximately 30 times greater than the approved clinical dose.

Administration, Oral↗