Biomedical subjects

J C Lamb

Publications and source records attributed to J C Lamb.

At least 37 records · Page 2Linked to original sources

PubMed1989

Reproductive toxicity of 2,2-bis(bromomethyl)-1,3-propanediol in a continuous breeding protocol in Swiss (CD-1) mice.

The effect of 2,2-bis(bromomethyl)-1,3-propanediol (BMP) on reproduction in Swiss CD-1 mice was evaluated by use of a continuous breeding protocol. BMP was administered in the feed at 0.1, 0.2, and 0.4% concentrations. Both male and female F0 mice (20 pairs per treatment group, 40 pairs of control animals) were dosed 7 days prior to and during a 98-day cohabitation period. Although the fertility index was unchanged in the high-dose group, BMP exposure significantly decreased the numbers of litters per pair, pups born alive per litter, and pup weight when adjusted for litter size. Crossover mating between treated and control F0 animals indicated a specific effect only on female reproductive capacity. At the highest dose, BMP caused a body weight decrease in the F0 animals of both sexes with no effect on relative organ weights. Sperm concentration, motility, morphology, and estrual cyclicity were unaffected by BMP exposure. Histopathology in the F0 animals revealed specific kidney lesions in both sexes; males were more sensitive than females. The last litter born in the 98-day breeding phase was reared to age 74 days and then mated to nonsiblings of the same treatment group. The effect of high-dose BMP exposure on F1 fertility, body and organ weights, sperm parameters, and estrual cyclicity was the same as that for the F0 animals, with the exception of the lack of renal lesions seen in the F1 females. These data show that BMP impaired fertility in female mice in both generations in the absence of an effect on reproductive organ weights and estrual cyclicity.

Animals↗

PubMed1989

Results and evaluations of 48 continuous breeding reproduction studies conducted in mice.

Results of 48 continuous breeding reproduction (RACB) studies are summarized and control data from these studies are used to determine the statistical sensitivity of each endpoint from different parts of these studies. Results of testing individual chemicals compared well with results of multigeneration studies reported in the literature. Continuous breeding studies were able to discriminate reproductive toxicants from nontoxicants, and provided valuable structure-activity information. When mice in continuous cohabitation produce multiple litters, the statistical sensitivity of fertility endpoints is quite high and is comparable to that associated with other sensitive indicators of reproductive function, such as testis weight and sperm parameter measures. The principal advantages of the RACB protocol in comparison to multigeneration studies are: (1) the increased sensitivity and statistical power, (2) the ability to monitor progression of toxicity and to detect subfertility, (3) use of a battery of endpoints including sperm measures, (4) the ability to determine the affected sex(es), and (5) slightly reduced testing time.

Animals↗

PubMed1988

Subchronic toxicity of orally administered (gavage and dosed-feed) theophylline in Fischer 344 rats and B6C3F1 mice.

Theophylline, a methylated xanthine closely resembling caffeine and theobromine, is a widely used pharmaceutical agent for the treatment of respiratory disorders and certain acute cardiovascular conditions. The National Toxicology Program has conducted 13-week subchronic toxicity studies in F344 rats and B6C3F1 mice (10 animals/group) following administration of theophylline via the diet or by gavage. Administration of theophylline in the feed (0, 1000, 2000, and 4000 ppm) resulted in no mortality or body weight effects in F344 rats, but did induce periarteritis of the arteries adjacent to mesenteric lymph nodes and the pancreas, particularly arterioles in the latter. Also observed in rats dosed with theophylline via the diet was an increased severity of chronic nephropathy in males, especially at the high dose. Administration of theophylline at the same concentrations in the feed to B6C3F1 mice resulted in no mortality, but terminal body weights were significantly decreased in all dosed groups. An increased incidence of hepatocellular glycogen depletion was observed in male and female mice, and this change is believed to represent a physiological alteration exacerbated by the administration of theophylline. Administration of theophylline by gavage to F344 rats (0, 37.5, 75, and 150 mg/kg) resulted in the early death of one high-dose male and female and significantly decreased or increased terminal body weights of high-dose males and females, respectively. Similar to the results of the dosed-feed study, male and female rats receiving theophylline by gavage demonstrated a dose-related increase in the incidence and severity of perivascular inflammation of mesenteric arteries. Gavage administration of theophylline to B6C3F1 mice (0, 75, 150, and 300 mg/kg) resulted in the early death of all high-dose females and 3/10 high-dose males and significant depression of terminal body weights in high- and mid-dose males and low-dose females. As in the dosed-feed study, the primary histopathologic change in the mouse subchronic gavage study was hepatocellular glycogen depletion, although in this case it was seen only in females. In summary, the major target organs for orally administered theophylline in 13-week subchronic toxicity studies appear to be the mesenteric arteries in F344 rats and the liver in B6C3F1 mice. On the basis of organ weight changes and/or minor histopathologic effects, many other tissues were also affected, particularly the kidneys in dosed-feed male rats and the uterus in gavage-dosed female rats.

Administration, Oral↗

PubMed1988

Comparison of changes in serum androgen binding protein with germinal epithelial damage and infertility induced by di-n-pentyl phthalate.

Androgen binding protein (ABP), produced by Sertoli cells and released into seminiferous tubules and blood, was measured in the serum of di-n-pentyl phthalate (DPP)-treated rats as a potential index of germinal epithelial damage. A single oral dose of DPP (0, 0.25, 1.0, or 2.0 g/kg body wt in corn oil) was given to four groups of 110 Fischer 344 rats; 10 rats per group were killed weekly for 10 weeks. Effects of treatment on serum ABP were then compared with effects on other reproductive endpoints. Treatment did not produce any significant effect on body weight or weights of liver, kidney, prostate, and seminal vesicles. In high-dose rats, serum ABP values more than doubled 2 days after injection, remained significantly elevated for 3 weeks, then fell and remained significantly below control values from Week 4 through Week 10. Accordingly, 95% of the rats in this group showed greater than 50% of the seminiferous tubules degenerated, decreased epididymal sperm density, reduced testicular and epididymal weights, and up to 97% morphologically abnormal sperm. In medium-dose rats, serum ABP increased up to 48% during the first week, returned to control values by Week 2, and remained at control levels thereafter. Of these rats, 20% showed 20-50% degenerated tubules, decreased sperm density, reduced testicular and epididymal weights (which were not always statistically significant), and up to 23% abnormal sperm morphology. In low-dose rats, serum ABP levels were similar to those of controls, and the other parameters, except sperm density, also remained unchanged. To examine the effects of DPP on fertility, a second group of rats was exposed in an identical manner [gavaged once with DPP in corn oil (0, 0.25, 1.0, and 2.0 g/kg body wt)], then mated to untreated females at 3, 6, and 10 weeks postexposure. DPP at 2 (but not 1.0 or 0.25) g/kg caused a significant reduction in pregnancies and live pups and a significant increase in preimplantation loss. Histopathology of the testis in the first experiment suggested a very slow recovery. Therefore, controls and high-dose rats in the mating trial were killed 14, 18, and 30 weeks after dosing and the germinal epithelium was evaluated histologically. All high-dose animals showed testicular lesions typical of phthalate ester exposure and the epithelium did not recover within 30 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

Androgen-Binding Protein↗

PubMed1988

Evaluation of two in vitro assays to screen for potential developmental toxicants.

To evaluate two in vitro assays for their ability to detect known developmental toxicants and nontoxicants, a series of 44 coded compounds were assayed by two independent laboratories using standardized protocols. The two test systems were (1) the human embryonic palatal mesenchymal cell growth inhibition assay and (2) the mouse ovarian tumor cell attachment inhibition assay. After all compounds were tested, they were decoded and ranked according to the minimum IC50 value (the millimolar concentration of compound which inhibits growth or attachment by 50% compared to the solvent control) from either test. The in vitro test result concordance with established in vivo animal and human test results was examined over a wide range of concentration levels (above which the in vitro results were called positive and below which they were considered negative). A positive response from either test was defined as a positive in vitro response. Concordance was defined as the number of correct responses divided by the number of chemicals tested. At the 1 mM level, the concordance of data from the combined in vitro assays with the in vivo data was 66% in one laboratory and 58% in the other. The maximum agreement between the combined in vitro and in vivo data was reached at the 20 mM level, where there was a 73 and 74% concordance of results in the two laboratories. At that level there was a 16 and 10% incidence of false negative results, and a 54 and 77% incidence of false positive results. A portion of these false negative compounds may require metabolic activation. The use of either assay alone was not as accurate as using a positive result from either test. Agreement of the in vitro data at the 10 mM level with available human data was 71 and 75% for each laboratory. The data indicate that the two assays are complimentary and as such the combination of these assays could be useful as a preliminary screen to establish priorities for in vivo developmental toxicity testing.

Animals↗

PubMed1988

Evaluation of rodent sperm, vaginal cytology, and reproductive organ weight data from National Toxicology Program 13-week studies.

Sperm morphology and vaginal cytology examinations (SMVCEs), which include evaluations of motility, concentration and head morphology of sperm from the cauda epididymis, and male reproductive organ weight data, were developed by the National Toxicology Program as a screening system for reproductive toxicants. An analysis was conducted of SMVCE studies carried out at the end of fifty 13-week studies (25 for rats, 25 for mice) over a 3-year period. Statistically significant changes in these studies were summarized, as were control data for each male endpoint (mean, SD, 95% confidence limits around the mean, median, and statistical power). Reproductive organ weights (testis, epididymis, cauda epididymis) and sperm motility were the most statistically powerful endpoints evaluated; sperm head morphology may also be a sensitive endpoint for detecting reproductive toxicants. For 24 chemicals tested in both rats and mice, the concordance of results [i.e., no adverse effect in either species, or at least one SMVCE endpoint (not necessarily the same one) adversely affected in both species] was 58%. These data suggest that detection of potential reproductive toxicants might be best when both species are used. Types of sperm head abnormalities and their relative proportion of the total did not differ among control and treatment groups. Estrous cycle data were obtained in the final week of forty-six 13-week studies (23 for mice, 23 for rats). Only 3 chemicals caused an increase in mean cycle length compared with the control group. More data from breeding studies in which female estrous cycle length is measured are needed to assess fully the association of cycle length with reproductive outcome; stages of the estrous cycle are so variable that they may not be useful in assessing potential toxicity. Interlaboratory variability in SMVCE values for many endpoints was documented. Very few of the chemicals that form the basis of this report have been evaluated in definitive reproductive toxicology protocols; a companion paper compares changes in SMVCE endpoints with the outcome of continuous breeding reproduction studies.

Animals↗

PubMed1988

Association of sperm, vaginal cytology, and reproductive organ weight data with results of continuous breeding reproduction studies in Swiss (CD-1) mice.

In continuous breeding reproduction studies in which an adverse effect on fertility was detected over an 18-week treatment period, a crossover mating trial was then conducted to determine the affected sex. Results of 25 crossover breeding studies conducted using Swiss (CD-1) mice were compared with results of sperm morphology and vaginal cytology examinations (SMVCEs) conducted at the conclusion of the mating trial. SMVCE endpoints include sperm concentration, motility, and morphology, vaginal cytology, and male reproductive organ weights. In most SMVCE studies multiple endpoints were adversely affected. For male reproductive toxicants, sperm motility was decreased in 89% of the studies, and absolute right epididymis and right testis weights were affected less frequently (80% each). Among studies with no detectable reduction in male breeding performance, 87% exhibited no detectable decrease in epididymis weight. Eighty-two percent had no change in cauda epididymis weight and 80% had no significant change in sperm concentration. An increase in female cycle length was associated (100%) with an effect on breeding due to female dysfunction. Overall accuracy, defined as correct identification of toxicants and nontoxicants, was highest for epididymis weight (84%), followed by cauda epididymis weight and sperm motility (79% each), and sperm concentration (76%). Female cycle length was so variable that the overall accuracy of the parameter in 13 studies was 69%. With the variety of chemicals used in this analysis, the association of abnormal sperm morphology with reproductive outcome was 71%. Control data (mean, 95% confidence interval around the mean, median, and statistical sensitivity) for each male endpoint (parent, and offspring at 10 weeks of age following a single breeding) were summarized from each of the two laboratories that conducted the studies. For several endpoints, statistical power was dependent on the laboratory conducting the studies. In general, the statistical sensitivity was relatively high for reproductive organ weights, although it was less for smaller organs such as the prostate. On the basis of both the biological and statistical analyses, it is recommended that multiple SMVCE endpoints, including sperm measures, be included in screens for reproductive toxicants.

Animals↗

PubMed1988

Studies on the short-term toxicity of theophylline in rats and mice.

The purpose of these studies was to evaluate the short-term toxicity of theophylline, a compound present in tea and used in a variety of clinical applications. Fourteen-day repeated-dose toxicity studies were conducted in B6C3F1 mice and F344 rats of both sexes. Theophylline was administered in feed (0, 500, 1000, 2000, 4000, and 8000 ppm) or by gavage in corn oil (12.5-twice daily, 25, 50, 50-twice daily, 100, 200, 200-twice daily, and 400 mg/kg). Dosed-feed exposure to theophylline at concentrations up to 8000 ppm induced no significant toxicity except for dose-related uterine hypoplasia in rats. Palatability problems at that level precluded administration of higher concentrations. In the gavage study, 400 mg/kg was acutely toxic for both species, but mice and rats differed in that this same daily dose administered as two separate doses of 200 mg/kg was acutely toxic in rats but not in mice. No dose-related weight gain depression was evident in mice; weight gain was depressed in the majority of dose levels in rats and was pronounced at the higher levels. Clinical signs in mice were squinting and distended testes in males, and in rats, rapid respiration (all doses), squinting, and hunching. Gross necropsies, organ weights, clinical pathology, and pathology identified no target organs in mice, while histopathologic observations in rats suggested heart and stomach as possible target organs. Histopathologic effects in a number of other tissues, including lung, thymus, bone marrow, spleen, and uterus, were considered to reflect agonal changes in treated rats, possibly related to inanition. The results suggest that both species and sex differences exist with respect to sensitivity to theophylline toxicity, with F344 rats being more sensitive than B6C3F1 mice and male rats being more sensitive than female rats.

Animals↗

PubMed1988

Reproductive effects of theophylline in mice and rats.

Theophylline was administered by gavage in 13-week studies to B6C3F1 mice (0, 75, 150, 300 mg/kg/day) and F344 rats (0, 37.5, 75, 150 mg/kg/day) with significant reductions in male mouse terminal body and testicular weights. Male rats also displayed reduced testicular weight, as well as nonsignificant but dose-related decreases in body weight. There was a significant but non-dose-related decrease in female mouse body weight. In parallel studies of B6C3F1 mice and F344 rats, theophylline administered in the diet (0, 0.1, 0.2, 0.4%) produced significantly decreased terminal body weights in male and female mice, but not rats. In rats, cauda epididymis weight was reduced at the high dose compared to the control group, and there was an increase in abnormal sperm. These studies were followed by continuous breeding reproductive assays in CD-1 mice in which theophylline was administered in feed (0.0, 0.075, 0.15, and 0.30%; calculated doses of 0, 125, 265, and 530 mg/kg/day, respectively) to breeding pairs for 14 weeks. There was a dose-dependent decrease in the number of live pups produced per litter, a significant decrease in the number of litters produced per pair (0.30%) and in the adjusted live pup weight (0.30%), a decrease in the percentage of pups born alive (0.15 and 0.30%), and an increase in the number of days needed to produce each litter (0.30%). After 19 weeks of continuous treatment at 0.30%, a crossover mating trial indicated that females and males were adversely affected by theophylline, as judged by the decreased percentage of pups born alive, the decreased live pup weight, and the decreased number of live pups per litter relative to matings within the control group, but the effects in females were more extensive. Based on other studies, there is a suggestion that the observed changes in fertility may be partially attributed to embryotoxicity.

Animals↗

PubMed1988

Reproductive toxicity of tricresyl phosphate in a continuous breeding protocol in Swiss (CD-1) mice.

The effects of a mixture of tricresyl phosphate isomers on reproductive performance in Swiss (CD-1) mice were evaluated using a continuous breeding protocol. Tricresyl phosphate (TCP) was mixed into the feed at 0, 0.05, 0.1, and 0.2% by weight. Although the fertility index was not changed in the animals consuming the high-concentration feed, the number of litters per pair decreased in a dose-related fashion, and the proportion of pups born alive, and their weight, was significantly decreased in the high-dose group. A crossover mating trial found impaired fertility in both males and females exposed to 0.2% TCP, with a greater effect in females. Histopathology of the F0 pairs revealed dose-related seminiferous tubule atrophy, and decreased testis and epididymal weights in the high-dose males, while the female reproductive tract showed no histopathologic changes. There were dose-related changes in the adrenals of both sexes, and body weight was depressed in both sexes at the highest concentration. The last litter born in the 98-day breeding phase was reared to age 74 days and then mated within the control and two of the treatment groups (0.0, 0.05, and 0.1% TCP; there were too few offspring in the 0.2% group). There was a decrease in the fertility index in the 0.1% TCP group, and a decreased proportion of liveborn and number of liveborn pups per litter. In the F1 males at necropsy, sperm concentration and morphology were normal at termination, although motility was decreased in both the 0.05% and the 0.1% groups compared to controls. These data show that TCP impaired fertility in both sexes of mice in the F0 generation and affected sperm motility at even the lowest dose in F1 males.

Adrenal Glands↗

PubMed1987

Reproductive tract lesions resulting from subchronic administration (63 days) of tri-o-cresyl phosphate in male rats.

An initial dose-range pilot study where animals were gavaged with between 100 and 1600 mg tri-o-cresyl phosphate (TOCP)/kg/day for 14 days resulted in decreased epididymal sperm density and disruption of the seminiferous epithelium in 100% of treated animals. A subchronic 63-day study (reflecting the 49-day length of the rat seminiferous epithelium cycle plus the 14-day transit time of spermatids through the epididymis was initiated. Dose-dependent (10 to 100 mg TOCP/kg/day) decreases in cauda epididymal sperm motility and density, testicular enzyme activities, and alterations in sperm morphology were observed. Concurrent pair-fed controls (matched to the highest dose group, 100 mg TOCP/kg/day) indicated that weight loss resulting from TOCP administration had minimal contributory effects to the testicular toxicity seen. Plasma alpha-tocopherol acetate (vitamin E) and testosterone concentrations were unaffected. Tri-p-cresyl phosphate (TPCP), the nonneurotoxic structural analog of TOCP, produced no toxic effects, demonstrating the necessity of the ortho-cresol moiety for induction of damage. A minimum effective (threshold) dose for observable testicular toxicity was determined to be 10-25 mg TOCP/kg in this study. These data suggest that TOCP interferes with spermatogenic processes and sperm motility directly and not via an androgenic mechanism or decreased vitamin E availability.

Animals↗

PubMed1987

Time course of the tri-o-cresyl phosphate-induced testicular lesion in F-344 rats: enzymatic, hormonal, and sperm parameter studies.

Tri-o-cresyl phosphate (TOCP), a known neurotoxic compound, causes testicular toxicity in both leghorn roosters and Fischer 344 rats. The present study was initiated to follow the onset of the testicular lesion through possible changes in sperm numbers and production, serum hormones, and various enzyme activities. Rats were administered TOCP daily (150 mg/kg) for periods of 3, 7, 10, 14, or 21 days. Vehicle-treated animals served as controls. Sperm motility and sperm number per milligram cauda epididymis were both lower in treated animals by Day 10. Testicular weight to body weight ratio was significantly decreased only in the longest treatment duration animals (21 days). Testicular neurotoxic esterase and nonspecific esterase activities were also inhibited, while beta-glucuronidase activity was not affected. Luteinizing and follicle-stimulating hormone levels were normal, as were both serum and interstitial fluid testosterone concentrations. Sertoli cell fluid secretion, as measured by testis weight increase after efferent duct ligation, showed no significant changes. Other organs (spleen, liver, kidney, pancreas, small intestine, adrenal and pituitary glands) had no overt signs of pathology as observed by light microscopy in animals treated for 21 days. A separate group of animals was treated for 21 days and subsequently examined after 98 days of observation (two cycles of the rat seminiferous epithelium). No recovery of spermatogenesis was seen, indicating that the toxicity was irreversible at the dose used. The effects noted in these studies further define the testicular lesion produced by TOCP and show that 150 mg/kg/day for 21 days produced irreversible testicular toxicity.

Animals↗

PubMed1987

Reproductive effects of four phthalic acid esters in the mouse.

These studies compared the reproductive toxicity of four phthalates by a continuous breeding protocol. Mice were given diets with diethyl phthalate (DEP) (0.0, 0.25, 1.25, or 2.5%), di-n-butyl phthalate (DBP) (0.0, 0.03, 0.3, or 1.0%), di-n-hexyl phthalate (DHP) (0.0, 0.3, 0.6, or 1.2%), or di(2-ethylhexyl) phthalate (DEHP) (0.0, 0.01, 0.1, or 0.3%). Both male and female CD-1 mice were dosed for 7 days prior to and during a 98-day cohabitation period. Reproductive function was evaluated during the cohabitation period by measuring the numbers of litters per pair and of live pups per litter, pup weight, and offspring survival. There was no apparent effect on reproductive function in the animals exposed to DEP, despite significant effects on body weight gain and liver weight. DBP exposure resulted in a reduction in the numbers of litters per pair and of live pups per litter and in the proportion of pups born alive at the 1.0% amount, but not at lower dose levels. A crossover mating trial demonstrated that female mice, but not males, were affected by DBP, as shown by significant decreases in the percentage of fertile pairs, the number of live pups per litter, the proportion of pups born alive, and live pup weight. DHP in the diet resulted in dose-related adverse effects on the numbers of litters per pair and of live pups per litter and proportion of pups born alive at 0.3, 0.6, and 1.2% DHP in the diet. A crossover mating study demonstrated that both sexes were affected. DEHP (at 0.1 and 0.3%) caused dose-dependent decreases in fertility and in the number and the proportion of pups born alive. A crossover mating trial showed that both sexes were affected by exposure to DEHP. These data demonstrate the ability of the continuous breeding protocol to discriminate the qualitative and quantitative reproductive effects of the more and less active congeners as well as the large differences in reproductive toxicity attributable to subtle changes in the alkyl substitution of phthalate esters.

Animals↗

PubMed1987

Testicular toxicity following oral administration of tri-o-cresyl phosphate (TOCP) in roosters.

Tri-o-cresyl phosphate (TOCP) is a neurotoxic organophosphorus compound that induces a characteristic central-peripheral distal axonopathy and Wallerian-type degeneration, 6-14 days after exposure. This organophosphorus compound-induced delayed neurotoxicity (OPIDN) has been extensively studied in the chicken, the standard test model. Reports of neurotoxic agents causing adverse effects on the male reproductive system initiated the present study which was designed to examine the effects of TOCP on the rooster. Previous work from this laboratory has demonstrated 100 mg TOCP/kg/day to be an OPIDN-inducing dose with minimal mortality in roosters. This dose level was administered to adult leghorn roosters (p.o., n = 10) for 18 consecutive days. By days 7-10 of the study, TOCP-treated birds exhibited limb paralysis characteristic of OPIDN. Analysis at termination revealed significant inhibition of neurotoxic esterase activity (NTE) in both brain and testis. There was also a slight decrease in brain acetylcholinesterase (AChe) activity. Sperm motility was shown to be greatly decreased. In addition, sections of formalin-fixed, methacrylate-embedded testes from TOCP-treated birds showed vacuolation of, and disorganization in the seminiferous epithelium. The marginal body weight decreases (17%) in treated animals were not considered to contribute to the testicular toxicity induced by TOCP. Parathion (O,O-diethyl-O-4-nitrophenyl phosphorothioate, 0.1 mg/kg/day, p.o., n = 3) was used as a positive control for AChE inhibition and a negative control for inducing OPIDN. Roosters treated continuously with parathion showed a decrease in brain AChE activity, but no changes in NTE, testicular histology, or limb function. These studies demonstrate the testicular toxicity of TOCP in roosters and suggest that this effect is not related to the chemical's anticholinergic action.

Animals↗

PubMed1986

Influence of dietary zinc on di(2-ethylhexyl)phthalate-induced testicular atrophy and zinc depletion in adult rats.

Groups of 48 adult male F344 rats were maintained on synthetic diets containing 20 ppm (normal), 2 ppm (low), or 200 ppm (high) zinc. After 1 week of acclimation to the various diets, groups of 12 rats from each dietary regimen were gavaged for 13 consecutive days with 0.0 (vehicle), 0.33, 1.0, or 3.0 g/kg di(2-ethylhexyl)phthalate (DEHP). These were selected as relatively nontoxic, mildly toxic, and moderately toxic doses for producing testicular injury in adult male rats. At termination on the 14th day, body weight gain was reduced by 3.0 g/kg DEHP dose in the normal and low-zinc diet groups but not in the high-zinc diet group. The low-zinc diet alone reduced body weight gain, independent of DEHP treatment. DEHP had no perceptible effects on the weights of testis, seminal vesicle, prostate, or epididymis from rats maintained on normal- or high-zinc diets, but reduced the weights of all of these organs from animals on the low-zinc diet in a dose-dependent manner. Lactate dehydrogenase activity, total and free sulfhydryl contents, and zinc concentrations in testes were also reduced, and testicular degeneration was induced by DEHP in the low-zinc diet groups. In contrast, dose-dependent liver enlargement and hypolipidemia (reduction of serum cholesterol and triglyceride concentrations) were produced by equivalent doses of DEHP in all of the three zinc groups. The selectively enhanced susceptibility of adult male F344 rats on a zinc deficient diet to the gonadotoxic effects of DEHP supports the hypothesis that testicular zinc depletion is causally related to the ensuing testicular and accessory sex organ atrophies. Other biological effects of DEHP (e.g., hypolipidemia, hepatomegaly) appear to occur independent of zinc homeostasis.

Animals↗

PubMed1986

Effects of thyroid hormones on the induction of cleft palate by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in C57BL/6N mice.

The induction of cleft palate by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) administered with thyroid hormones triiodothyronine (T3) or thyroxine (T4) was investigated in C57BL/6N mice. Timed-pregnant mice were treated with vehicle, TCDD, T3, T4, TCDD plus T3, or TCDD plus T4 on Days 10 to 13 of gestation. No cleft palates were observed in any control fetuses in this study, nor have there been any cleft palates in 1193 fetuses or 154 control litters in the past 24 months. TCDD (3 micrograms/kg/day) caused about 8% cleft palates per litter, while T3 (120, 240, 480 micrograms/kg/day) and T4 (625, 1250, 2500 micrograms/kg/day) resulted in no more than 1.2% cleft palates per litter in any of the treatment groups and the incidence was not dose related. The combination of TCDD (3 micrograms/kg/day) plus T3 at 120, 240, and 480 micrograms/kg/day resulted in 15.9, 20.6, and 31.4% cleft palates per litter, respectively. TCDD plus T4 at 625, 1250 and 2500 micrograms/kg/day caused 15.1, 22.9, and 27.2% cleft palates per litter. No cleft palates were observed when large doses of T3 were given in combination with T4. These data demonstrated that coadministration of T3 or T4 with TCDD increased the incidence of cleft palate to incidences greater than expected from the separate administration of the hormones plus TCDD.

Animals↗

PubMed1986

Synergistic interaction of 2,3,7,8,-tetrachlorodibenzo-p-dioxin and hydrocortisone in the induction of cleft palate in mice.

Glucocorticoids cause cleft palate in sensitive mouse strains by interfering with the proliferation of mesenchymal cells in the palatal shelves; 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) also causes cleft palate, but its effects involve the epithelial cells. The purpose of this study was to examine the interaction of TCDD and the glucocorticoid hydrocortisone in the induction of malformations. Pregnant C57BL/6N mice were treated on gestation days 10-13 with TCDD (0 or 3 micrograms/kg, p.o.), hydrocortisone (0, 25, 50, or 100 mg/kg, s.c.) or a combination of TCDD and hydrocortisone. The dams were killed on gestation day 18 and the mice were analyzed for maternal and fetal toxicity and soft tissue malformations. TCDD alone had no effect on litter size, fetal weight or viability, or maternal weight gain. This dose of TCDD is essentially a threshold dose and it did not produce cleft palate in this study, but all the TCDD-treated fetuses had hydronephrosis, the most sensitive indicator of TCDD teratogenicity. Hydrocortisone alone caused dose-related decreases in fetal weight and maternal liver/body weight ratios, and dose-related increases in cleft palate (0, 5, 10, and 30%). No effects of hydrocortisone were detected on litter size or fetal viability, but maternal weights were affected. Combination of all doses of hydrocortisone with TCDD resulted in a 100% incidence of cleft palate, accompanied by a decrease in litter size and fetal weight and an increase in fetal mortality related to the dose of hydrocortisone. TCDD tended to reverse the decrease in liver/body weight ratio seen with hydrocortisone alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗

PubMed1986

Reproductive toxicology of methyldopa in male F344/N rats.

Methyldopa, a widely used antihypertensive drug, was administered to male Fischer 344/N rats by gavage 5 days/week for 65 days at dosages of 0, 50, 100, 200, or 400 mg/kg. Decreased body weight was seen in treated animals. After mating to untreated female Fischer 344/N rats on days 57-61, the male rats were necropsied (days 65-67) and reproductive toxicity was measured by sperm count, sperm motility, organ weights, hormone levels and histologic evaluation of the testis. Decreased fertility was seen in males dosed with 200 or 400 mg/kg methyldopa. Decreases were also seen in sperm count, sperm motility, apparent number of late spermatids, and plasma testosterone levels in males in the 200 and 400 mg/kg groups. This alternation of reproductive function in male rats was found to be reversible after a 13-week recovery period without dosing. The marked decrease in circulating testosterone levels following methyldopa treatment at 200 or 400 mg/kg may have contributed to the reproductive toxicity of this drug.

Animals↗