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Biomedical subjects

J Ashby

Publications and source records attributed to J Ashby.

At least 73 records · Page 4Linked to original sources
PubMed1999

Lack of effects for low dose levels of bisphenol A and diethylstilbestrol on the prostate gland of CF1 mice exposed in utero.

vom Saal et al. (Proc. Natl. Acad. Sci. 94, 2056-2061, 1997) have reported that low dose exposure (0.02-2 microg/kg/day) of CF1 mice to diethylstilbestrol (DES) in utero led to increases in the prostate gland weight when the pups reached 8 months of age. Nagel et al. (Environ. Health Perspect. 105, 70-76, 1997) reported similar effects in CF1 mice at 6 months of age after exposure in utero to low dose levels (2 and 20 microg/kg/day) of bisphenol A (BPA). vom Saal et al. (Toxicol. Indust. Health 14(1/2) 239-260, 1998) subsequently reported reduced sperm efficiency (daily sperm production per gram testes) in a subset of the BPA animals for which enlarged prostates had been observed. These three experiments have been repeated in a single experiment that was terminated when the offspring reached 6 months of age. No statistically significant effects on prostate weight or sperm efficiency were recorded for offspring of animals exposed to either DES (0.2 microg/kg/day) or BPA (2 and 20 microg/kg/day) in utero. Significant dam effects were seen for several of the assay parameters indicating that the litter, as opposed to the individual, should be considered as the statistical unit in such experiments. A statistically significant increase in body weight was recorded for the low dose BPA male offspring. Females from the study underwent normal sexual maturation and showed no significant differences in reproductive tissue weights at termination and the mean day of vaginal opening. The possible reasons for this failure to confirm the earlier reported effects for DES and BPA at these low doses are discussed.

Animals↗
PubMed1999

Safety evaluation of phytosterol esters. Part 1. Assessment of oestrogenicity using a combination of in vivo and in vitro assays.

Phytosterols are natural constituents of the human diet, and as part of an extensive programme of safety evaluation studies investigating their use as a novel food ingredient, the possible oestrogenic effects of phytosterols have been investigated using a combination of in vitro and in vivo assays. Competitive binding with the immature rat uterine oestrogen receptor (ER) has been used to measure the ability of phytosterols to bind to ERs while the transcriptional activation of oestrogen-responsive genes has been examined in an oestrogen-inducible yeast screen. Phytosterols did not display any activity in these in vitro assays. Uterotrophic assays have been conducted to investigate the potential for phytosterols to elicit an oestrogenic response when administered orally to immature female rats (n = 10) at doses of 0, 5, 50 or 500 mg/kg/day for 3 consecutive days. Phytosterols (a well characterized mixture of beta-sitosterol, campesterol and stigmasterol) and phytosterol esters (the previous phytosterol mixture esterified with fatty acids from sunflower oil) did not exhibit oestrogenic activity in the immature female rat using uterine wet weight as the endpoint. Beta-oestradiol (0.4 mg/kg/day) consistently produced a significant increase in uterus weights. Coumestrol (a known phytoestrogen) was also tested as a weak positive control and produced a dose response at doses of 20, 40 and 80 mg/kg/day in the uterotrophic assay. In conclusion, we have shown that phytosterols do not bind to the ER and do not stimulate transcriptional activity of the human ER in a recombinant yeast strain. In addition, there was no indication of oestrogenicity from the uterotrophic assay when the material was administered by oral gavage to immature female rats.

Administration, Oral↗
PubMed1999

Antimicrobial resistance in gram-positive pathogens isolated in the UK between October 1996 and January 1997.

Antimicrobial resistance in gram-positive pathogens from 30 centres in the UK (ten Teaching, ten Associate Teaching and ten District General Hospitals) was studied over a 4 month period between October 1996 and January 1997. High-level resistance (HLR) and low-level resistance (LLR) to penicillin amongst pneumococci was 3.3% and 3.4%, respectively. However, considerable variation in resistance rates was observed depending on geographical location (LLR range 0-15.4% and HLR range 0-30.8%). Considerable variation in resistance rates was also observed for Staphylococcus aureus to methicillin, with rates ranging from 0% to 56.7% depending on locality. Using conventional MIC methodology, none of the isolates of S. aureus was considered as having reduced sensitivity to vancomycin. However, eight isolates grew on Brain Heart Infusion Agar containing vancomycin (4 mg/L) after prolonged incubation and are therefore worthy of further investigation by electron microscopy. With Enterococcus faecalis, resistance rates were similar between the three types of hospital and only four isolates were considered resistant to glycopeptide antibiotics (one vanA and three vanB phenotype).

Anti-Bacterial Agents↗
PubMed1999

Induction of hyperplasia and increased DNA content in the uterus of immature rats exposed to coumestrol.

Administration of the phytoestrogen coumestrol to ovariectomized rats leads to increases in both wet and dry uterine weights in the absence of an increase in uterine DNA content, as reported by Markaverich et al. [Effects of Coumestrol on Estrogen Receptor Function and Uterine Growth in Ovariectomized Rats. Environ Health Perspect 103:574-581 (1995)]. It was not possible to know if the observed atypical uterotrophic response of coumestrol was associated uniquely with the ovariectomized uterotrophic assay protocol. This question is answered in the present paper. Two experiments are described in which three daily oral gavage administrations of 60 mg/kg/day coumestrol to immature AP rats were followed by assessment of the reproductive tract on the fourth day. In both experiments coumestrol increased uterine fluid content and increased the weights of the uterus, cervix, and vagina. In addition, bromodeoxyuridine staining of uterine sections enabled confirmation of uterine hyperplasia for the coumestrol-treated animals. In the second experiment, total uterine DNA was determined; it doubled in the coumestrol-treated animals. Estradiol benzoate acted as the positive control agent for both of these experiments, and in each case it gave similar responses to those seen for coumestrol. We conclude that the uterotrophic activity of the phytoestrogen coumestrol in the immature intact rat is typical of the activity of the natural estrogen estradiol.

Animals↗
PubMed1999

Hepatic gene mutations induced in Big Blue rats by both the potent rat liver azo-carcinogen 6BT and its reported noncarcinogenic analogue 5BT.

The potent rat liver carcinogen 6-p-dimethylaminophenylazobenzthiazole (6BT) and its reported noncarcinogenic analogue 5-p-dimethylaminophenylazobenzthiazole (5BT; evaluated for carcinogenicity under the similar limited bioassay conditions used for 6BT) have been studied in order to seek an explanation for their different carcinogenic activities. Both compounds act as DNA-damaging agents to the rat liver, and both have now been shown to induce lacI (-) gene mutations in the liver of Big Blue(trade mark) transgenic rats. Both compounds were mutagenic following ten daily gavage doses or following administration in diet for 10 days. Neither chemical induced cell proliferation in the liver following repeat gavage administrations. In contrast, dietary administration of 6BT, and to a lesser extent of 5BT, induced hepatic cell proliferation. The carcinogen 6BT, but not the noncarcinogen 5BT, caused proliferation of oval stem cells in the livers by both routes of administration. It is possible that mutations induced in oval cells by 6BT are responsible for its potent carcinogenicity, and that the comparative absence of these cells in 5BT-treated livers may account for the carcinogenic inactivity of 5BT. Equally, the proliferation of the oval cells may reflect changes in liver homeostasis associated with the liver toxicity observed at the dose level of 6BT used (which was, nonetheless, the dose level used in the positive cancer bioassays). It is concluded that the new data presented cannot explain the differing carcinogenic activities of 5BT and 6BT, and that the reported noncarcinogen 5BT may also be carcinogenic when adequately assessed for this activity.

Animals↗
PubMed1998

An assessment of the genetic toxicology of antimony trioxide.

Antimony trioxide (Sb2O3, CAS 1309-64-4) has been examined in a range of in vitro and in vivo genotoxicity assays. Negative results were obtained with the Salmonella/microsome assay and the L5178Y mutation assay, but a positive response was observed in the in vitro cytogenetic assay using isolated human peripheral lymphocytes. However, in vivo, antimony trioxide was non-clastogenic in the mouse bone marrow micronucleus assay, following oral gavage administration for 1, 7, 14 or 21 days at dose levels of up to 5000 mg/kg (single dose) or 1000 mg/kg (repeat dose). A negative result was also obtained in the in vivo rat liver DNA repair (unscheduled DNA synthesis) assay following a single oral gavage administration of doses up to 5000 mg/kg. These data show no genotoxicity for antimony trioxide in vivo and do not confirm a previous report of clastogenicity in the mouse on repeated dosing. It is concluded that antimony trioxide is not genotoxic in vivo and does not present a genotoxic hazard to humans.

Animals↗
PubMed1998

Mutagenicity of the human bladder carcinogen 4-aminobiphenyl to the bladder of MutaMouse transgenic mice.

The human carcinogen 4-aminobiphenyl (4AB) was evaluated in the MutaMouse transgenic mouse mutation assay. A single oral dose of 75 mg/kg induced 6.9-, 1.8- and 2.2-fold increases in the mutation frequency (MF) in the bladder, liver and bone marrow, respectively. Ten daily oral doses of 10 mg/kg 4AB increased the MF in the bladder, liver and bone marrow by 13.7-, 4.8- 2.4-fold the control value, respectively. The repeat dosing protocol was therefore more sensitive than the single dose protocol. Assessment of DNA samples prepared from pooled liver homogenates clearly indicated the increase in MF observed in the individual liver samples obtained from both groups of 4AB-treated mice.

Aminobiphenyl Compounds↗
PubMed1998

Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic.

The inadvertent estrogenicity of certain synthetic chemicals, and their subsequent effects on the endocrine system of humans and wildlife, is of concern. In this paper we report findings from in vitro and in vivo (uterotrophic) studies which confirm that a range of alkyl hydroxy benzoate preservatives (parabens) are weakly estrogenic. In a receptor-binding assay, butylparaben was able to compete with 3H-estradiol for binding to the rat estrogen receptor with an affinity approximately 5 orders of magnitude lower than that of diethylstilboestrol, and between 1 and 2 orders of magnitude less than nonylphenol. In an in vitro yeast-based estrogen assay, the four most widely used parabens (namely methyl-, ethyl-, propyl-, and butylparaben) were all found to be weakly estrogenic with the most potent (butylparaben) being 10,000-fold less potent than 17 beta-estradiol. The estrogenic activity of parabens was inhibited by 4-hydroxy tamoxifen in vitro, illustrating the requirement of these chemicals to interact with the estrogen receptor in order to activate the yeast. When administered orally to immature rats, the parabens were inactive. However, subcutaneous administration of butylparaben produced a positive uterotrophic response in vivo, although it was approximately 100,000 times less potent than 17 beta-estradiol. Given their use in a wide range of commercially available topical preparations, it is suggested that the safety in use of these chemicals should be reassessed, with particular attention being paid to estimation of the actual levels of systemic exposure of humans exposed to these chemicals. The acquisition of such data is a prerequisite to the derivation of reliable estimates of the possible human risk of exposure to parabens.

Animals↗
PubMed1998

Mutagenicity of ethyl carbamate to lacZ- transgenic mice.

The mutagenicity of the rodent carcinogen ethyl carbamate (EC, urethane) has been assessed using the lacZ- transgenic mouse mutation assay (Muta Mouse). In two separate experiments a single i.p. dose of 900 mg/kg urethane followed by a 14-16 day expression period yielded statistically significant (approximately 2-fold) increases in mutation frequency (MF) in the lung and liver of the mice. In the second experiment MF in the spleen and bone marrow was also assessed and statistically significant increases in MF were observed in each case. Concomitantly conducted bone marrow micronucleus assays gave 15.8- and 8-fold increases respectively in the incidence of micronucleated polychromatic erythrocytes in the two studies.

Animals↗
PubMed1998

Uterotrophic activity of bisphenol A in the immature rat.

Bisphenol A (BPA) is active in immature AP rat uterotrophic assays when evaluated using either the oral or the subcutaneous (sc) injection routes of exposure (three daily administrations of 400-800 mg/kg BPA). Premature vaginal opening was seen for 8 of 14 animals exposed to 600 and 800 mg/kg BPA by sc injection. Vaginal opening was not produced by BPA in the gavage studies. These results are consistent with those of Dodds and Lawson [Nature 137:96 (1936)] who found that BPA induces persistent vaginal cornification in ovariectomized rats exposed to three twice-daily injections of 85 mg/kg BPA (total daily dose 170 mg/kg), but they conflict with the reported inactivity of BPA in the immature mouse uterotrophic assay. The uterotrophic activity of diethylstilbestrol in the rat is also established (0.04 mg/kg/day for three days).

Administration, Oral↗
PubMed1998

Relative activities of methyl methanesulphonate (MMS) as a genotoxin, clastogen and gene mutagen to the liver and bone marrow of MutaMouse mice.

The mutagenicity of the rodent carcinogen methyl methanesulphonate (MMS) to the liver and bone marrow of MutaMouse lacZ- transgenic mice was evaluated. A single intraperitoneal (i.p.) dose of 100 mg/kg MMS gave a strong positive response in the liver UDS and bone marrow micronucleus assays conducted 2 hr and 30 hr, respectively, after dosing. A single i.p. administration of 100 mg/kg of MMS, or five daily administrations of 20 mg/kg MMS, failed to increase significantly the lacZ- --> lacZ+ mutation frequency (MF) in either the liver or the bone marrow, albeit some evidence of weak mutagenicity was observed for the liver. The gene mutation analyses were undertaken 14 days after the final chemical exposure. Administration of the liver mitogens dimethylnitrosamine (DMN), or 4-acetylaminofluorene (4AAF), subsequent to multiple (five) exposures of 20 mg/kg MMS, foiled to enhance the mutagenicity of MMS to the liver, thereby eliminating the possibility that MMS produced promutagenic lesions in the liver that were not transformed to mutations because of the absence of MMS-induced cell division. In the latter experiments, DMN gave a strong mutagenic response and 4AAF a weak mutagenic response. Possible reasons for this selective mutagenicity of MMS (DNA damage and micronuclei induction in the absence of gene mutations) are discussed, but no clear outcome emerges. It is concluded that transgenic mutation assays should not be employed for defining genetic toxicity in vivo, but rather should be reserved for mechanistic studies on previously established rodent genotoxins and/or carcinogens.

2-Acetylaminofluorene↗
PubMed1997

Thalidomide: lack of mutagenic activity across phyla and genetic endpoints.

The human and rabbit teratogen thalidomide has been tested for mutagenicity in a wide range of assays, ranging from bacterial gene mutation assays conducted in vitro to in vivo cytogenetic assays conducted using rabbits, and including a variety of human-derived tissues. Thalidomide was not mutagenic to 6 strains of Salmonella when tested both in the presence and absence of Aroclor-induced rat liver S9 mix. This inactivity was confirmed in strains TA98 and TA100 using a 1-h pre-incubation assay protocol with the same S9 mix (10% S9), and additionally, in strain TA98 using 3 concentrations of S9 (4%, 10% and 30% S9 in S9 mix). Thalidomide was not clastogenic either to cultured human lymphocytes (whole blood cultures, minus S9 mix) or to Chinese hamster ovary (CHO) cells treated in vitro. Further, no cytotoxicity was observed in purified human lymphocytes when exposed to thalidomide up to the limit of its solubility in the medium in the presence and absence of liver S9 from Aroclor-induced pregnant rabbit. The CHO assays were conducted without metabolic activation and in the presence of a variety of sources of auxiliary metabolic activation (PB/beta NP-induced rat liver S9 mix, pooled male and female human liver S9 mix, uninduced and Aroclor-induced pregnant rabbit liver S9 mix and foetal rabbit S9 mix). Thalidomide did not induce micronuclei in isolated human lymphocytes (minus S9 mix) and it was non-mutagenic to mouse lymphoma L5178Y TK+/- cells when tested to the limits of its solubility in the culture medium (+/- S9 mix). No indication of recombinogenic or clastogenic activity was observed for thalidomide when tested in Drosophila. In addition, it failed to induce chromosome aberrations in grasshopper neuroblasts when tested in the presence and absence of Aroclor-induced rat liver S9 mix. Some unusual chromosome morphologies were observed in the grasshopper cytogenetic preparations indicating a potential of thalidomide to interact with chromosomal proteins. However, this potential was not evident in the human lymphocyte micronucleus assay, and thalidomide was apparently not reactive to the proteins of the mouse skin, as it gave negative results in a mouse local lymph node assay for skin sensitizing agents. Thalidomide was inactive in bone marrow micronucleus assays conducted using males and females from two strains of mice, and female New Zealand white rabbits. It is concluded that thalidomide is neither a mutagen nor an aneugen. This conclusion is discussed within the context of the results of earlier mutagenicity studies, the recent claim that thalidomide may be a heritable germ cell mutagen to humans, and the current interest in thalidomide for the treatment of immune system-related diseases.

Abnormalities, Drug-Induced↗
PubMed1997

Lack of activity of estradiol in rodent bone marrow micronucleus assays.

Estradiol has been evaluated in five independent rodent bone marrow micronucleus assays and has been found to be inactive. The dose-range evaluated extended from three daily doses of 20 micrograms/kg to the rat, a regimen that elicited a potent uterotrophic response from the animals, to single doses of between 10-150 mg/kg to the mouse. The mouse assays simulated and extended the conditions of test employed by earlier investigators who had found estradiol, and three structurally-related synthetic estrogens, to be active in mouse micronucleus assays over the dose range 1-10 mg/kg. It is concluded that estradiol is not genotoxic to the bone marrow of rodents. The top dose-level used in the present micronucleus assays (150 mg/kg) represented approximately 150,000 times the minimum estrogenic dose of this chemical to rodents, and that was considered to be above the dose at which useful genetic toxicity data would be generated for this potent estrogen. The maximum tolerated dose (MTD) of estradiol to rodents remains to be established.

Animals↗