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P M Foster

Publications and source records attributed to P M Foster.

54 records · Page 3Linked to original sources
PubMed1983

The morphological development of di-N-pentyl phthalate induced testicular atrophy in the rat.

Prepubertal rats treated orally with di-n-pentyl phthalate at 2.2 g/kg body weight were killed at 1, 3, 6 and 24 hr following a single dose, and after 2, 3 and 4 days of repeated daily dosing. At 3 hr Sertoli cells in a proportion of the seminiferous tubules showed vacuolation of the perinuclear smooth endoplasmic reticulum with an associated inward displacement of germinal cells. By 6 hr the vacuolation had extended to the apical cytoplasm and was evident in most tubules. Early degenerative changes were also apparent in spermatocytes and spermatids and were accompanied by an acute interstitial inflammatory infiltrate. By 24 hr, germinal cell degeneration was extensive with desquamation and general disorganisation of cell layers within the epithelium, but the interstitial inflammatory infiltrate had declined. Mitochondrial succinic dehydrogenase activity in Sertoli cells was reduced at 3 and 6 hr and absent by 24 hr. In germinal cells it was unaffected at 3 and 6 hr but absent by 24 hr. Two, three and four days of daily phthalate treatment resulted in a gradual depletion of germinal cells from all tubules, leaving a Sertoli cell matrix containing a few necrotic spermatocytes and occasional normal spermatogonia. The significance of the early Sertoli cell changes is discussed.

Animals↗
PubMed1983

Testicular toxicity of ethylene glycol monomethyl and monoethyl ethers in the rat.

Ethylene glycol monomethyl (EGM) and monoethyl (EGE) ethers were administered po to rats at dosages varying from 50 to 500 mg/kg body weight/day for EGM and 250 to 1000 mg/kg body weight/day EGE for 11 days. First evidence of testicular damage following EGM treatment was observed 24 hr after a single dose of 100 mg/kg body weight when the lesion appeared localized in the primary spermatocyte. At 16 hr after a single dose of 500 mg/kg, mitochondrial damage was one of the first subcellular changes to be demonstrated. Treatment of animals with EGE resulted in a similar lesion; however, to obtain damage of equivalent severity, a larger dosage for a longer period was required. In limited studies with 2-methoxy- and 2-ethoxyacetic acids (putative metabolites of EGM and EGE, respectively), using equimolar doses to their parent compounds (500 mg EGM or EGE/kg for 4 or 11 days, respectively) gave damage of equivalent severity to the corresponding glycol ether. After dosing animals with 500 mg EGM/kg body weight for 4 days, the testes recovered weight, and the majority of tubules recovered their spermatogenic potential within one full maturation cycle. The recovery study also indicated a possible effect on the spermatogonia in a small number of tubules although no morphological abnormalities to this cell type could be observed. No effect levels over the 11-day treatment period were 50 and 250 mg/kg body weight/day for EGM and EGE, respectively.

Animals↗
PubMed1983

Effect of DI-n-pentyl phthalate treatment on testicular steroidogenic enzymes and cytochrome P-450 in the rat.

Treatment of young male rats with dipentyl phthalate (DPP) produced significant decreases in testicular cytochrome P-450, cytochrome P-450 dependent microsomal steroidogenic enzymes (17 alpha-hydroxylase, 17-20 lyase) and in the maximal binding of a natural substrate (progesterone) to testis microsomes. No effect was demonstrated by this compound on hepatic cytochrome P-450 content. Treatment of animals with a phthalate ester not causing testicular atrophy (diethyl phthalate; DEP) produced no significant changes in any of the parameters measured. This effect on the enzymes responsible for androgen production may be important as a mechanism of action involved in the development of phthalate-induced testicular damage.

Animals↗
PubMed1982

Species differences in the testicular toxicity of phthalate esters.

Oral administration of di-n-butylphthalate (DBP) produced uniformly severe seminiferous tubular atrophy in rats and guinea pigs but caused only focal atrophy in mice. Hamsters showed no testicular changes with DBP and only minor changes in response to di-(2-ethylhexyl)phthalate (DEHP) and di-n-pentylphthalate (DPP). The rate of intestinal monohydrolysis of DEHP was slower in hamsters than in rats and this may be important, as mono-(2-ethylhexyl)phthalate (MEHP) did cause focal seminiferous tubular atrophy in hamsters. However, mono-n-butylphthalate (MBP) had no such effect. The decrease in testicular zinc concentration and enhancement of urinary zinc excretion produced in rats by DEHP and DPP was not observed in hamsters. Thus, species differ widely in their sensitivity to the testicular toxicity of phthalate esters.

Animals↗
PubMed1981

Studies on the testicular effects and zinc excretion produced by various isomers of monobutyl-o-phthalate in the rat.

Mono-n-butyl, -iso-butyl, -sec-butyl or -tert-butyl esters of o-phthalic acid were orally administered at 800 mg/kg body wt./day for 6 days, to young male rats. All of the animals except those treated with the mono-tert-ester developed marked testicular atrophy. Additionally, only those isomers producing testicular damage were found to alter zinc metabolism by increasing the urinary excretion of zinc and by depleting the concentration of this element in testicular tissues.

Animals↗
PubMedDate not supplied

Testicular toxicity of 2-methoxyacetaldehyde, a possible metabolite of ethylene glycol monomethyl ether, in the rat.

2-Methoxyacetaldehyde (MALD) was shown to produce specific cellular toxicity to pachytene spermatocytes in mixed testicular cell cultures as evidenced by morphological changes to these cells, an increase in germ-cell detachment and leakage of the pachytene spermatocyte marker enzyme lactate dehydrogenase-X. These effects occurred at concentrations where the known testicular toxicant, 2-methoxyacetic acid (MAA) was without effect (0.2 and 0.5 mM). In vivo, MALD also produced the characteristic testicular lesion reported previously for MAA and its parent compound ethylene glycol monomethyl ether (EGME). It is likely that MALD plays an important role in EGME-induced testicular toxicity.

Acetaldehyde↗
PubMedDate not supplied

Prioritization of NTP reproductive toxicants for field studies.

Population studies that evaluate human reproductive impairment are time consuming, expensive, logistically difficult, and with limited resources must be prioritized to effectively prevent the adverse health effects in humans. Interactions among health scientists, unions, and industry can serve to identify populations exposed to potential hazards and develop strategies to evaluate and apply appropriate controls. This report describes a systematic method for prioritizing chemicals that may need human reproductive health field studies. Rodent reproductive toxicants identified from the National Toxicology Program (NTP) Reproductive Assessment by Continuous Breeding (RACB) protocol were prioritized on the basis of potency of toxic effect and population at risk. This model for prioritization links NTP findings with data from the National Occupational Exposure Survey (NOES) and the Hazardous Substance Data Base (HSDB) or the High Production Volume Chemical Database (HPVC) to prioritize chemicals for their potential impact on worker populations. The chemicals with the highest priority for field study were: dibutyl phthalate, boric acid, tricresyl phosphate, and N, N-dimethylformamide.

Animals↗
PubMedDate not supplied

Leydig cell hyperplasia and adenoma formation: mechanisms and relevance to humans.

Leydig cell adenomas are observed frequently in studies evaluating the chronic toxicity of chemical agents in laboratory animals. Doubts have been raised about the relevance of such responses for human risk assessment, but the question of relevance has not been evaluated and presented in a comprehensive manner by a broad group of experts. This article reports the consensus conclusions from a workshop on rodent Leydig cell adenomas and human relevance. Five aspects of Leydig cell biology and toxicology were discussed: 1) control of Leydig cell proliferation; 2) mechanisms of toxicant-induced Leydig cell hyperplasia and tumorigenesis; 3) pathology of Leydig cell adenomas; 4) epidemiology of Leydig cell adenomas; and 5) risk assessment for Leydig cell tumorigens. Important research needs also were identified. Uncertainty exists about the true incidence of Leydig cell adenomas in men, although apparent incidence is rare and restricted primarily to white males. Also, surveillance databases for specific therapeutic agents as well as nicotine and lactose that have induced Leydig cell hyperplasia or adenoma in test species have detected no increased incidence in humans. Because uncertainties exist about the true incidence in humans, induction of Leydig cell adenomas in test species may be of concern under some conditions. Occurrence of Leydig cell hyperplasia alone in test species after lifetime exposure to a chemical does not constitute a cause for concern in a risk assessment for carcinogenic potential, but early occurrence may indicate a need for additional testing. Occurrence of Leydig cell adenomas in test species is of potential concern as both a carcinogenic and reproductive effect if the mode of induction and potential exposures cannot be ruled out as relevant for humans. The workgroup focused on seven hormonal modes of induction of which two, GnRH agonism and dopamine agonism, were considered not relevant to humans. Androgen receptor antagonism, 5 alpha-reductase inhibition, testosterone biosynthesis inhibition, aromatase inhibition, and estrogen agonism were considered to be relevant or potentially relevant, but quantitative differences may exist across species, with rodents being more sensitive. A margin of exposure (MOE; the ratio of the lowest exposure associated with toxicity to the human exposure level) approach should be used for compounds causing Leydig cell adenoma by a hormonal mode that is relevant to humans. For agents that are positive for mutagenicity, the decision regarding a MOE or linear extrapolation approach should be made on a case-by-case basis. In the absence of information about mode of induction, it is necessary to utilize default assumptions, including linear behavior below the observable range. All of the evidence should be weighed in the decision-making process.

Adenoma↗
PubMedDate not supplied

Fertility and developmental neurotoxicity effects of inhaled hydrogen sulfide in Sprague-Dawley rats.

In this study, we examined whether perinatal exposure by inhalation to hydrogen sulfide (H2S) had an adverse impact on pregnancy outcomes, offspring prenatal and postnatal development, or offspring behavior. Virgin male and female Sprague-Dawley rats (12 rats/sex/concentration) were exposed (0, 10, 30, or 80 ppm H2S; 6 h/day, 7 days/week) for 2 weeks prior to breeding. Exposures continued during a 2-week mating period (evidence of copulation = gestation day 0 = GD 0) and then from GD 0 through GD 19. Exposure of dams and their pups (eight rats/litter after culling) resumed between postnatal day (PND) 5 and 18. Adult male rats were exposed for 70 consecutive days. Offspring were evaluated using motor activity (PND 13, 17, 21, and 60+/-2), passive avoidance (PND 22+/-1 and 62+/-3), functional observation battery (PND 60+/-2), acoustic startle response (PND 21 and 62+/-3), and neuropathology (PND 23+/-2 and 61+/-2). There were no deaths and no adverse physical signs observed in F0 male or female rats during the study. A statistically significant decrease in feed consumption was observed in F0 male rats from the 80-ppm H2S exposure group during the first week of exposure. There were no statistically significant effects on the reproductive performance of the F0 rats as assessed by the number of females with live pups, litter size, average length of gestation, and the average number of implants per pregnant female. Exposure to H2S did not affect pup growth, development, or performance on any of the behavioral tests. The results of our study suggest that H2S is neither a reproductive toxicant nor a behavioral developmental neurotoxicant in the rat at occupationally relevant exposure concentrations (< or =10 ppm).

Administration, Inhalation↗
PubMedDate not supplied

Effects of phthalate esters on the developing reproductive tract of male rats.

Phthalate esters are a large group of chemical agents used predominantly as plasticizers and solvents. Certain members of this chemical class have been shown to cause reproductive and developmental toxicity. Recent attention has focused on the potential of these agents to interfere with male reproductive development through a postulated antiandrogenic mechanism. Observations have focused on di-n-butyl phthalate (DBP), di-(2-ethylhexyl) phthalate (DEHP) and butyl benzylphthalate, with most information relating to dose-response relationships obtained for DBP. Neither DBP, DEHP nor their major metabolites interacted with human or rodent androgen receptors (AR) in transcriptional activation assays. DBP was administered during the critical window of development of the male reproductive system, after which the resulting offspring were examined until adulthood. DBP elicited marked effects on the developing male reproductive tract, including malformations of the epididymis and vas deferens, and hypospadias. Retention of thoracic nipples/areolae and reductions in anogenital distance were also noted. Surprisingly, Leydig cell adenomas were induced in some male offspring at 100 days of age. All these events occurred in the absence of any toxicity in the pregnant dam. Examination of testes from fetal rats indicated markedly reduced testosterone levels and increased Leydig cell numbers after DBP administration to the dams. Leydig cells were positive for AR and 3-betahydroxysteroid dehydrogenase.

Aging↗
PubMedDate not supplied

Differences in urinary metabolic profile from di-n-butyl phthalate-treated rats and hamsters. A possible explanation for species differences in susceptibility to testicular atrophy.

A high-performance liquid chromatographic method for the direct analysis of the urinary metabolites of di-n-butyl phthalate (DBP) is described. In both rats and hamsters the major urinary metabolite found after treatment with either DBP or mono-n-butyl phthalate (MBP) was MBP glucuronide and not MBP as previously reported. The levels of unconjugated MBP in the urine of animals treated with DBP or MBP were three- to fourfold higher in the rat than in the hamster. However, intestinal esterase activities were comparable in the two species, whereas the activities of testicular beta-glucuronidase were significantly higher in rats compared to hamsters. It is possible that the differences in the concentration of free MBP, a substance known to produce testicular damage directly in the rat in vitro, may account for the lack of injury seen in hamsters after oral treatment with either DBP or MBP.

Animals↗
PubMedDate not supplied

Detection of germ cell-derived proteins in testicular interstitial fluid: potential for monitoring spermatogenesis in vivo.

The aim of the present study was to assess whether proteins secreted by the seminiferous tubules (ST) can be detected in testicular interstitial fluid (IF) and testicular (TV), spermatic (SV), and peripheral venous (PV) plasma from adult rats. An antiserum was raised against seminiferous tubule-conditioned medium (STCM) prepared from adult rats and used in conjunction with Western blot analysis to screen IF and blood samples resolved by one-dimensional (1-D) and two-dimensional (2-D) sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Samples of IF and PV were analyzed from control adult rats and rats exposed to scrotal heating (43 degrees C for 30 minutes) 24 hours earlier to ascertain whether damage to spermatogenesis would affect 'leakage' of proteins from the seminiferous tubules. In all control rats, the STCM antiserum specifically detected three proteins in testicular IF with molecular weights of 24, 16, and 14 kDa, respectively. Heat treatment increased the abundance of these proteins and induced the appearance of several other less-abundant proteins, all with molecular masses below 25 kDa. Two of the proteins present in IF were identified, the 24-kDa protein as phosphatidylethanolamine-binding protein (PEBP), and the 14-kDa protein as an androgen-regulated protein (ARP-2). Both of these proteins have been shown in previous studies to be secreted by round spermatids. Our results suggest that germ cell secretory products can gain access to the interstitium under both normal physiological conditions and more easily after induction of damage to spermatogenesis. The antiserum was unable to detect any ST-derived proteins in blood, although it is likely that this result may be due to insensitivity of the presently used techniques. The development of specific immunoassays for germ cell-secreted proteins (e.g., PEBP and ARP-2) should enable more definitive assessment of whether proteins secreted by the seminiferous epithellum can be measured in blood and thus provide a potential means of monitoring spermatogenesis.

Animals↗