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Biomedical subjects

R E Chapin

Publications and source records attributed to R E Chapin.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1985

Effects of ethylene glycol monomethyl ether (EGME) on mating performance and epididymal sperm parameters in F344 rats.

Previous histologic studies on the effects of EGME identified dividing spermatocytes as a primary target cell type in the testis. The following studies were undertaken to assess possible effects of EGME on late-stage and epididymal spermatids, and spermatogonia. Adult male F344 rats (n = 20/group) of proven fertility were dosed po with 0, 50, 100, or 200 mg EGME/kg/day for 5 days. Each male was then mated with two females/week for 8 weeks. Females were sacrificed ca. 2 weeks after removal from the male, and number of live and dead fetuses, resorption sites, and corpora lutea were noted. Additional males were treated similarly, sacrificed at weekly intervals, and measures of epididymal sperm count, motility, and morphology were made. The fertility of males treated with 200 mg EGME/kg declined at Week 4, and remained low for the rest of the study. There was a modest but significant increase in the number of resorption sites at Weeks 5 and 6 in the high dose group. There was a decrease in the number of litters sired at Week 5 after dosing in the 100-mg EGME/kg group. There were time- and dose-related decreases in sperm concentration and motility, primarily in the 100- and 200-mg/kg groups, as well as concurrent elevations in the number of abnormal sperm forms in the epididymis. These studies show that EGME is a very weak inducer of dominant-lethal mutations, and produces previously undescribed effects on late-stage spermatids and spermatogonia.

Animals↗
PubMed1985

The recovery of the testis over 8 weeks after short-term dosing with ethylene glycol monomethyl ether: histology, cell-specific enzymes, and rete testis fluid protein.

Ethylene glycol monomethyl ether (EGME) has been found to affect meiotic spermatocytes, spermatids, other stages of spermatocytes, and spermatogonia, depending on the dose used. These studies, which examine testicular recovery from EGME treatment, analyzed tissues from rats treated for 5 days with 0, 50, 100, or 200 mg EGME/kg/day and sacrificed at eight subsequent weekly intervals; some epididymal sperm parameters of these animals have been described. Histologically, the testes of the low-dose group showed very mild changes, while the 100- and 200-mg/kg groups showed widespread damage and cell death which recovered somewhat during the course of the study. There was no treatment-related effect on seminal vesicle or prostate weights. Rete testis fluid protein levels were changed only in the high-dose group, when protein levels rose to a maximum of sixfold the control values at Week 4; by Week 6, there was no difference between groups. Changes in cell-specific enzyme activities were dose dependent and generally mirrored changes in the number of germ cells in the testis.

Acid Phosphatase↗
PubMed1984

Development of reproductive tract lesions in male F344 rats after treatment with dimethyl methylphosphonate.

Dimethyl methylphosphonate (DMMP) is an organophosphorous compound that impairs fertility in male rodents. In previous studies, male rats treated with DMMP had decreased sperm motility and count, and sired fewer litters with fewer pups per litter. The following studies examined the development of the reproductive lesions by light and electron microscopy after treatment with DMMP. Adult male F344 rats were treated po with DMMP, 1750 mg/kg, for up to 12 weeks. Tissues were perfused in situ with Karnovsky's fixative and embedded in glycol methacrylate. After 5 weeks of treatment there were occasional PAS-positive bodies in lumina of tubules in stages XII-III. These were ultrastructurally similar to cytoplasm of step 12-17 spermatids. After 7 weeks of treatment, there was an increase in the number of tubules exhibiting these bodies, as well as an increase in the number of tubules showing delayed or early spermiation, or focal exfoliation of nonnecrotic cap-phase spermatids and some spermatocytes. No multinucleated giant cells were seen. Focal loss of germ cells occurred more frequently as duration of exposure increased, and occupied 5-100% of an affected tubule. Frequently, an area of germ cell exfoliation occurred adjacent to areas of normal tubular epithelium. These lesions were not specific to any particular stages of spermatogenesis. Occasionally, elongating spermatids were without rib elements of the fibrous sheath in the tail; these were not seen in epididymal sections. Animals left to recover for 14 weeks after treatment showed approximately 80% normal tubules; affected tubules varied in their degree of recovery, but all showed the loss of normal epithelial organization, a characteristic of DMMP treatment. Epididymal epithelium was not visibly affected by treatment with DMMP. DMMP produced morphologic alterations in Sertoli cells and elongating spermatids, as well as producing functional defects in spermatozoa.

Animals↗
PubMed1984

Studies of lesions induced in the testis and epididymis of F-344 rats by inhaled methyl chloride.

Experiments were carried out in rats to characterize the development of the testicular and epididymal lesions and any associated effects on reproductive hormones. Adult F-344 rats were exposed to 3500 ppm methyl chloride (MeCl) 6 hr/day for 5 days, not exposed for 3 days, and exposed again for 4 days. The first consistent testicular lesion was a delay in spermiation which appeared on Day 9. Subsequently, germinal epithelial vacuolation and cellular exfoliation became widespread as exposure continued. All animals killed after 19 days also displayed bilateral epididymal granulomas in regions 5 or 6 of the cauda epididymis. The nature and distribution of inflammatory cells indicated that the primary neutrophilic response may be against the tubular epithelium and not extravasated sperm. After 5 days of exposure, circulating testosterone was below 6 ng/ml (control: 120 +/- 31 ng/ml). Both MeCl exposed and control animals responded similarly to challenge with hCG and LHRH ethylamide, suggesting that Leydig cell and gonadotrope function was unaffected. It is proposed that MeCl acts centrally to lower circulating testosterone. Nonprotein sulfhydryls were depleted in liver, testis, and epididymis after MeCl exposure, but not in whole blood. This finding indicates that sulfhydryl depletion is not due to direct alkylation, but is enzymatically mediated. Sulfhydryl depletion did not correlate with lesion development. It was concluded that the initial testicular effects of MeCl are directed at either the late stage spermatids or the Sertoli cells with a resultant delay in spermiation.

Animals↗
PubMed1984

Immersion fixation methods for glycol methacrylate-embedded testes.

Routine processing of testicular tissue through 10% neutral buffered formalin (NBF) into paraffin produces severe cellular shrinkage which obscures most of the morphologic detail. The following studies were performed to compare different combinations of immersion fixatives and embedding media for optimal cellular detail in the final histologic sections. We examined sections of testes from rats, mice, and rabbits fixed in either NBF, Bouin's, Zenker's, or Helly's fixatives, and embedded in either standard paraffin or glycol methacrylate. The results were similar in all 3 species. In paraffin, Bouin's or Helly's fixatives produced the fewest artifacts, while in glycol methacrylate, NBF-fixed tissue showed the greatest intracellular detail and preservation. The merits and limitations of each method are discussed for the rat, with exceptions for the other species noted where appropriate. The use of glycol methacrylate as the support medium for sectioning makes high-quality tissue sections available from formalin-fixed testes.

Acrylates↗
PubMed1984

Effects of ethylene glycol monomethyl ether on various parameters of testicular function in the F344 rat.

These studies were designed to define the target cell for ethylene glycol monomethyl ether (EGME) action in the rodent testis, and to compare fluid production and protein secretory patterns in the testes of treated and control animals. Adult F344 rats were treated with 150 mg/kg/day, 5 day/week, and sacrificed 1, 2, 4, 7 or 10 days after the first dose. In the testes of treated animals, the most sensitive cells were the premeiotic and meiotic spermatocytes. As length of treatment continued, the younger transitional spermatocytes, and more pachytene spermatocytes, were affected. Early and late stage spermatids did not appear affected, nor was the visual appearance of spermatogonia changed by exposure to EGME. Fluid production, androgen-binding protein secretion and electrophoreograms of proteins found in the ligated rete testis were also unchanged by EGME, showing that these indices of Sertoli cell function were not affected by EGME. The histologic and biochemical data suggest that both early and late spermatocytes are targets for EGME in the testis, and that the Sertoli cells are relatively unaffected.

Androgen-Binding Protein↗
PubMed1983

The morphogenesis of testicular degeneration induced in rats by orally administered 2,5-hexanedione.

The neurotoxic hexacarbon 2,5-hexanedione (2,5-HD) produces testicular atrophy in experimental animals. To examine the morphogenesis of the testicular lesion, 1.0% 2,5-HD was provided in the drinking water of adult F-344 rats for up to 6 weeks. After 3 weeks of administration, there were occasional large vacuoles in the basal region of the germinal epithelium. At 4 weeks, these vacuoles were much larger and more numerous; electron microscopy demonstrated that they were derived from the smooth endoplasmic reticulum. The vacuoles were preferentially associated with stages 12, 13, 14, and 1 of the spermatogenic cycle. Additionally, at 4 weeks there was a significant decrease in the number of tubules in stages 7 and 13, and a concomitant increase in the percentage of tubules in stages 3, 5, and 6. By Week 5, most Golgi-phase and cap-phase spermatids were visibly affected, showing margination of nuclear chromatin, and were becoming dissociated from Sertoli cells. Frequent multinucleated giant cells were seen and electron microscopy of these cells suggested that they were derived from fused spermatocytes or spermatids. After 6 weeks, fewer giant cells were present, most tubules contained cellular debris, and many showed empty lumina encircled by a thin ring of cytoplasm near the basement membrane. Interstitial tissue appeared unaffected. These studies indicate that the Sertoli cell is probably an initial target for 2,5-HD action in the testis.

Animals↗
PubMed1982

Dopamine antagonists do not block testosterone-induced decrease in luteinizing hormone.

These studies were designed to test the hypothesis that testosterone might lower circulating levels of luteinizing hormone (LH) in castrated male rats by activating dopaminergic neuronal systems. Blood samples were drawn from conscious rats through an indwelling cannula during the fourth and eight hours after subcutaneous administration of testosterone (1 or 5 mg/kg, in corn oil). Testosterone caused a dose-dependent decrease in plasma LH levels eight hours after administration. This decrease was not blocked by prior administration of the dopaminergic antagonists haloperidol and flupenthixol. This lack of effect of dopaminergic antagonists indicates that testosterone does not act primarily via dopaminergic activation to lower LH.

Animals↗
PubMed1981

Antagonism of ethanol-induced decrease in LH by para-chlorophenylalanine: lack of correlation with altered serotonergic mechanisms.

Acute administration of ethanol lowers plasma levels of luteinizing hormone (LH) in several species. Since ethanol may interact with central serotonergic (5HT) neurons, and since 5HT systems have been found to play a role in modulating LH release, we examined the possible role of central serotonergic neurons in the ethanol-induced depression of LH. Acute PCPA (400 mg/kg, 20 hr before 2.0 g/kg ethanol) was effective in preventing the ethanol-induced depression of LH, suggesting that ethanol activates 5HT systems to lower LH. In support of this, the central 5HT agonist 5-methoxy-N, N-dimethyltryptamine (5MDMT) depressed LH in a dose-dependent manner. However, while the effects of a sub-maximal dose of 5MDMT were blocked by prior administration of methysergide, this 5HT receptor antagonist was unable to prevent the post-ethanol fall in LH. Additionally, because other doses of PCPA (250 mg/kg 20 hr prior to ethanol, and 100 mg/kg P.O. x 3 days before ethanol) produced similar reductions in hypothalamic 5HT but did not block the ethanol effect, and because electrolytic lesions of the median raphe nucleus were also ineffective in preventing the post-ethanol depression of LH, we conclude that activation of serotonergic systems does not play a major role in the ethanol induced depression of LH.

5,7-Dihydroxytryptamine↗
PubMed1981

Effects of acute and chronic 1,3-butanediol treatment on central nervous system function: a comparison with ethanol.

In the present investigation, the neuropharmacology of 1,3 butanediol (1,3-BD) was compared with that of ethanol. Acute i.p. administration of equimolar doses of 1,3-BD or ethanol to rats impaired the aerial righting reflex, attenuated the suppressive effect of punishment on drinking behavior, lowered blood pressure, caused a concomitant reduction in the content of guanosine 3',5'-monophosphate in the cerebellum and reduced ethanol withdrawal reactions. Although these data suggested that ethanol and 2,3-BD were of similar potency, the brain content of 1,3-BD was only 33% of that of ethanol after treatment with equimolar doses, suggesting a greater central nervous system (CNS) potency for 1,3-BD. In rats treated chronically with ethanol to produce physical dependence, 1,3-BD was more potent than ethanol in inhibiting the hyperexcitability observed upon ethanol withdrawal. Furthermore, chronic administration and withdrawal of 1,3-BD caused CNS hyperexcitability in rats that was characteristic of physical dependence. Despite these similarities, there were clear differences in the actions of ethanol and 1,3-BD. In mice, locomotor stimulation caused by ethanol was not observed after 1,3-BD. Furthermore, while 1,3-BD did not alter the concentration of luteinizing hormone in plasma, equivalent doses of ethanol markedly reduced the concentration of this hormone. These data indicate that like ethanol, 1,3-BD depresses CNS activity and induces physical dependence, but has less effect on plasma luteinizing hormone concentration than ethanol.

Animals↗