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Biomedical subjects

J Ashby

Publications and source records attributed to J Ashby.

At least 361 records · Page 20Linked to original sources
PubMed1977

Skeletal status in mentally retarded patients on anticonvulsive therapy.

X-ray densitometric measurement of radius mineral content and radiogrammetry of the cortical index of the second metacarpal were made on 644 institutionalized mentally retarded males and females, 224 of whom had received long-term anticonvulsant drug treatment. Analysis of variance of radius mineral content and metacarpal cortical index indicated that values for mentally retarded persons are not significantly different from the normal-for-age values. Radius density among anticonvulsant males, however, was significantly lower than that of non-anticonvulsant males in four out of five age groups. Among females the anticonvulsant patients were not significantly lower in radius density than the non-anticonvulsant females. Similar trends were evident in cortical indices of the second metacarpal: Two out of five age groups of anticonvulsant males were significantly lower than non-anticonvulsant males, while only one of five age groups of anticonvulsant females was significantly lower than non-anticonvulsant females. The effects of diphenylhydantoin and phenobarbital are similar in their adverse effects on bone growth and development.

Absorptiometry, Photon↗
PubMed1976

Evaluation of six short term tests for detecting organic chemical carcinogens and recommendations for their use.

Six short term tests for detecting carcinogenicity have been evaluated using 120 compounds, of which half were carcinogens and the rest non-carcinogens. The results obtained indicate that the Ames test and a "cell transformation" assay are both sufficiently sensitive to carcinogenicity, or the lack of it, in the compounds studied to enable them to be employed for detecting potential carcinogens. The consequences of using short term tests under various screening conditions have been explored. In order to have confidence in the results obtained for new or previously untested compounds it is important to use such tests in a carefully controlled manner.

Alkylating Agents↗
PubMed1970

John, 17 months.

Explore the source record for details and available documents.

Child, Hospitalized↗
PubMedDate not supplied

Partial and weak oestrogenicity of the red wine constituent resveratrol: consideration of its superagonist activity in MCF-7 cells and its suggested cardiovascular protective effects.

It was recently reported that the red wine phytoestrogen resveratrol (RES) acts as a superagonist to oestrogen-responsive MCF-7 cells. This activity of RES was speculated to be relevant to the 'French paradox' in which moderate red wine consumption is reported to yield cardiovascular health benefits to humans. We report here that RES binds to oestrogen receptors (ER) isolated from rat uterus with an affinity approximately 5 orders of magnitude lower than does either the reference synthetic oestrogen diethylstilboestrol (DES) or oestradiol (E2). In comparison with E2 or DES, RES is only a weak and partial agonist in a yeast hER-alpha transcription assay and in cos-1 cell assays employing transient transfections of ER-alpha or ER-beta associated with two different ER-response elements. Resveratrol was also concluded to be inactive in immature rat uterotrophic assays conducted using three daily administrations of 0.03-120 mgkg(-1)/day(-1) RES (administered by either oral gavage or subcutaneous injection). These data weaken the suggestion that the oestrogenicity of RES may account for the reported cardiovascular protective effects of red wine consumption, and they raise questions regarding the extent to which oestrogenicity data derived for a chemical using MCF-7 cells (or any other single in vitro assay) can be used to predict the hormonal effects likely to occur in animals or humans.

Animals↗
PubMedDate not supplied

Effects of p-nonylphenol (NP) and diethylstilboestrol (DES) on the Alderley Park (Alpk) rat: comparison of mammary gland and uterus sensitivity following oral gavage or implanted mini-pumps.

An earlier report by Colerangle and Roy indicated that administration of p-nonylphenol (NP) to Noble rats, via subcutaneously implanted mini-pumps at estimated doses of 53.2 and 0.073 mg kg(-1) day(-1) for 11 days, led to proliferation of the mammary gland. Those results indicated a ca. 600-fold enhancement in assay sensitivity to NP over that of the standard 3-day rat uterotrophic assay. The potential importance of these observations led us to repeat the experiments in the Noble rat, as described earlier. Although our earlier results confirmed the reported effects of diethylstilboestrol (DES) on the mammary gland of Noble rats, we found no effects with NP. The present report extends our investigations of the effects of NP and DES on the mammary gland and uterus of other rat strains using both oral dosing and exposure via mini-pumps. The 3-day oral uterotrophic assay responses to NP were similar for immature Alderly Park (Alpk; Wistar-derived) and immature Sprague-Dawley rats. Likewise, oral administration of NP to ovariectomized Alpk rats for 11 days gave responses of a similar magnitude to those seen in the 3-day immature assays and in earlier 3-and 11-day oral assays conducted using Noble rats. Administration of NP via mini-pumps to ovariectomized Alpk rats, at the implant doses employed by Colerangle and Roy, gave a negative uterotrophic response. The highest achieved dose levels of NP in the implant experiment (27 mg kg(-1) day(-1)) were lower than in the above assays and the negative response was therefore consistent with the previously defined minimum detection level for NP in the uterotrophic assay of ca. 40 mg kg(-1) day(-1) day(-1). It is concluded that the uterotrophic activity of NP is independent of the strain of rat, the duration of dosing and the route of exposure. Two mammary gland studies were conducted on NP and DES in the Alpk rat. In the first study (a repeat of the techniques used in earlier studies with the Noble rat), NP was administered via mini-pumps (achieved doses of 0.052 and 37.4 mg kg(-1) day(-3) NP) and produced no effect on mammary gland development, whereas DES gave the expected trophic response. In the second mammary gland study, NP was administered orally to Alpk rats at 100 mg kg(-1) day(-1) for 11 days (a dose that produced a positive uterotrophic response in ovariectomized rats). In this experiment, DES, and to a lesser extent NP, increased mammary gland differentiation and cell proliferation. The present studies have demonstrated that the rat mammary gland responds predictably to oestrogenic stimulation but does not show increased sensitivity to oestrogens when compared to the rat uterus. It is also concluded that the minimum detection level for oestrogenic responses of NP in rodents, following oral, dietary and implant routes of exposure, is ca. 40 mg kg(-1) day(-1).

Administration, Oral↗
PubMedDate not supplied

The peripubertal male rat assay as an alternative to the Hershberger castrated male rat assay for the detection of anti-androgens, oestrogens and metabolic modulators.

A range of chemicals with various levels of activity as actual or potential endocrine disrupters have been evaluated for activity in the peripubertal male rat assay. The chemicals studied included anti-androgens (vinclozolin), cyproterone acetate, flutamide, 2, 2-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE), metabolic modulators (anastrazole, finasteride, ketoconazole) and oestrogens (butyl benzyl phthalate (BBP), methoxychlor, bisphenol A (BPA), diethylstilboestrol (DES)), the suspected anti-androgen dibutyl phthalate (DBP) and the non-oestrogen fenitrothion. Dosing extended over postnatal days (pnd) 22-35, 36-50, 36-55 and 22-35, with recovery to pnd 55 or 22-55. The endpoints studied were changes in the weights of testes, epididymides, seminal vesicles and prostate. Changes in body weight and the weights of the liver and kidney were also monitored. In some experiments changes in the day of prepuce separation (PPS) were also determined. Only BBP and BPA were inactive in all the assays conducted. Changes in the weight of reproductive tissues provided a sensitive indicator of activity for the remaining chemicals with the exception of DDE, for which higher dose levels could have been used. However, none of the curtailed periods of exposure were able to detect all of the agents. Diethyl stilboestrol, and to a lesser extent DBP and DDE, delayed PPS when exposure occurred over the period pnd 22-55. A complex dependence of the day of PPS on the period of exposure and the body weight of the test animals was observed, and caution is recommended when assessing this endpoint in the presence of reductions in body weight. It is concluded that reproductive tissue weight changes in the peripubertal male have shown sensitivity to a range of biochemical modulators, oestrogens and anti-androgens, and that as such the assay warrants further evaluation. Measurement of delays in PPS may be of value in cases of large delays, but delays of 1-2 days will be difficult to interpret with confidence. The present results are discussed within the context of the sexually mature male rat assay described by O'Connor and the castrated male rat assay described by Hershberger, both of which are the subject of current international study. It is concluded that a decision on the usefulness of the peripubertal male rat assay must await the generation of further data on each of these three assays. There is an urgent need for international agreement on a list of reference endocrine disrupters and their active dose levels, with which to validate individual endocrine disruption assays and batteries of assays.

Anastrozole↗
PubMedDate not supplied

Possible androgenic/anti-androgenic activity of the insecticide fenitrothion.

To date, within the field of endocrine disruption, much focus has been placed on chemicals that mimic oestrogens (so-called xenoestrogens), and the number of such chemicals apparently detected continues to grow steadily. Less effort has been expended on investigating chemicals that mimic, or antagonize, other hormones. Nevertheless, a number of chemicals have been reported to have a weak affinity for the androgen receptor, all of which have, to date, been found to have anti-androgenic activity in vivo. In this report, we present evidence that the insecticide fenitrothion can interact with the androgen, but not with the oestrogen, receptor. Using recombinant yeast expressing the human androgen receptor, we found that fenitrothion behaved as an androgen agonist in vitro when tested alone, and that it could antagonize the androgen DHT when both chemicals competed for the androgen receptor in vitro. In vivo studies using both intact and castrated male rats showed no conclusive androgenic or anti-androgenic responses. Changes in organ weights suggestive of anti-androgenic effects were mitigated against by the reduced body weights of fenitrothion-treated rats. The toxicity of the compound precluded the use of higher dose levels to substantiate any tentative findings. Interestingly, fenitrothion (and related insecticides) is structurally similar to flutamide, an anti-androgen used clinically that gives clearly positive responses in both intact and castrated rats.

Androgens↗
PubMedDate not supplied

Concomitant observations of UDS in the liver and micronuclei in the bone marrow of rats exposed to cyclophosphamide or 2-acetylaminofluorene.

Oral dosing of between 5-30 mg/kg of cyclophosphamide (CP) to Alderley Park rats induced micronuclei in the bone marrow between 12 and 36 h after dosing, but failed to induce unscheduled DNA synthesis (UDS) in the liver at similar dose levels and treatment periods. Dose levels of greater than 30 mg/kg were toxic to the liver. In contrast, 2-acetylaminofluorene (2AAF) induced UDS in the rat liver between 4-36 h after dosing, but gave only a weak response in the bone marrow assay at dose levels between 0.5 and 2 g/kg. Selected observations were made for each chemical using both tissues of the same test animal. It is concluded that an assessment of the genotoxicity in vivo of chemicals defined as genotoxic in vitro will contribute to an assessment of their possible mammalian carcinogenicity, and that these should involve assays conducted using both the bone marrow and the liver of rodents. Due to its relative ease of commission, the bone marrow micronucleus assay will usually be conducted first; in the case of negative results it is recommended that a liver genotoxicity assay should be conducted. The case for employing in vivo short-term genotoxicity tests to predict the possible organotropic carcinogenicity or germ cell mutagenicity of a new in vitro genotoxin is discussed.

2-Acetylaminofluorene↗
PubMedDate not supplied

The non-genotoxicity to rodents of the potent rodent bladder carcinogens o-anisidine and p-cresidine.

The two potent rodent bladder carcinogens o-anisidine and p-cresidine, and the structurally related non-carcinogen 2,4-dimethoxyaniline, have been extensively evaluated for genotoxicity to rodents and found to be inactive. Most data were generated on o-anisidine, an agent that is also only marginally genotoxic in vitro. The two carcinogens induced methaemoglobinaemia in rodents indicating that the chemicals are absorbed and metabolically oxidized. Despite their total lack of genotoxicity in vivo, the two carcinogens have the hall-marks of being genotoxic carcinogens given that most test animals of both sexes of B6C3F1 mice and F344 rats are reported to have succumbed rapidly to malignant bladder cancer. No reasons for this dramatic conflict of test data are so far apparent. The experiments described involve, in one or other combination, 2 strains of mice (including B6C3F1) and 4 strains of rat (including F344), the use of oral and i.p. routes of exposure and observations made after 1, 3 or 6 doses of test chemical. 6 tissues (including the rat bladder) were assayed using 3 genetic endpoints (unscheduled DNA synthesis, DNA single-strand breaks and micronuclei induction). Aroclor-induced rats were employed in one set of experiments with o-anisidine. In the case of one set of mouse bone-marrow micronucleus experiments the same batch of the 3 chemicals as used in the cancer bioassays, and the same strain of mouse, were used. Possible further experiments and the implications of these findings are discussed.

Aniline Compounds↗