Biomedical subjects

R K Miller

Publications and source records attributed to R K Miller.

153 records · Page 9Linked to original sources

PubMedDate not supplied

Placental toxicity of cadmium in the rat: an ultrastructural study.

Pregnant rats on day 18 of gestation were injected s.c. with 40 mumol/kg CdCl2 which caused fetal death and placental necrosis. The placental changes were studied by electron microscopy and indicate that there is a direct placental toxic effect of cadmium which appears targeted at the trophoblast and, in particular, trophoblast cell layer II. Findings in cell layer II which suggest a toxic effect were lysosomal vesiculation, 'buckshot' nuclear chromatin clumping, nucleolar changes and apparent mitochondrial calcification. Furthermore, the selectivity of the effect on cell layer II and the rapidity of the necrosis are also consistent with a toxic effect. Trophoblast cell layer II first undergoes necrosis, but is rapidly followed by the rest of the trophoblast. Many of the changes at this necrotic stage suggest a secondary ischaemic effect or a combined ischaemic and toxic effect. Therefore it appears that cadmium induces placental necrosis via a direct effect on the trophoblast, especially on layer II.

Animals↗

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Robert L. Brent.

Explore the source record for details and available documents.

History, 20th Century↗

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Teratogenicity of methanol following a single oral dose in Long-Evans rats.

The teratogenicity of methanol was investigated following a single oral exposure preceded by an equal volume of mineral oil to guard against local gastric irritation. Four groups of pregnant Long-Evans rats were gavaged on day 10 of gestation with the following solutions: 0.0 (n = 13), 1.3 (n = 12), 2.6 (n = 11), and 5.2 (n = 10) mL MeOH/kg. Wilson sectioning (head only), gross necropsy, and Alizarin red skeletal examinations were performed on day 20 of gestation. At 5.2 mL/kg, the dams demonstrated > 20% decrease in weight gain in comparison to the control, which was the only clinical toxic manifestation or histopathologic change noted for the dams. Methanol at all doses failed to produce any significant change in standard reproductive indices (e.g., postimplantation loss). A significant decrease in fetal body weight (11 to 19.5%), however, was associated with prenatal oral ingestion of methanol. Both internal and external examination of the fetuses demonstrated a dose-dependent increase in anomalies [0 = 0.6%, 1.3 mL/kg = 3.7%, 2.6 mL/kg = 7%, 5.2 mL/kg = 16.5% (litter percents)]. The dose-related anomalies were undescended testes, exophthalmia, and anophthalmia. Thus, acute methanol given orally produces anomalies, even when there is no apparent maternal toxic response.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Periconceptional vitamin A use: how much is teratogenic?

The objective of the review is to determine whether preformed vitamin A (retinol and retinyl esters) is teratogenic at dosages commonly used by women living in industrialized countries. Published human and animal data and research developed by the authors are reviewed. It is well known that vitamin A is essential for normal reproduction and development. Although doses of 10,000 IU/d or less of preformed vitamin A (retinyl esters and retinol) are considered safe, doses > 10,000 IU/d as supplements have been reported to cause malformations in a single epidemiologic study. Nonhuman primate data show no teratogenicity at doses of 30,000 IU/d. Daily periconceptional exposures greater than 25,000 IU/d of preformed vitamin A have not been sufficiently studied to establish specific risk. Because no study reports adverse effects of 10,000 IU/d preformed vitamin A supplements and this dose is more than the Recommended Dietary Allowance for pregnant women (2670 IU or 800 RE/d), we recommend that women living in industrialized countries or who otherwise have nutritionally adequate diets may not need to ingest more than the Recommended Dietary Allowance of preformed vitamin A as supplements. If periconceptional vitamin A exposures to levels up to 30,000 IU/d (9,000 micrograms RE/d) do occur unintentionally, multiple animal studies do support only very low risk. Human epidemiologic studies do not establish at what level vitamin A becomes teratogenic; however, pharmacokinetic data presented in this paper indicate that blood levels of retinoids from women taking 30,000 IU/d of preformed vitamin A are not greater than retinoid blood levels in pregnant women during the first trimester who delivered healthy babies. Interestingly, neither teratogenicity nor vitamin A toxicity has been observed in multiple species exposed to high doses of beta-carotene.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Free vitamin B12 and transcobalamin II-vitamin B12 complex uptake by the visceral yolk sac of the Sprague-Dawley rat: effect of inhibitors.

Exogenous free vitamin B12 or B12 bound to human transcobalamin II (TCII) accumulated in the near-term rat visceral yolk sac. The rates of their uptakes in vitro and in vivo increased rapidly with time then reached a plateau, which supports a saturable transport/binding process as the rate-limiting step for the uptake of free and TCII complexed B12. Both uptakes were significantly decreased by trypan blue, colchicine, and low temperature but not by ouabain. Such inhibition suggests that the absorption of free and bound B12 is via an endocytosis process dependent upon energy but not the magnesium-dependent sodium/potassium-activated ATPase. Thus, the role of the visceral yolk sac in vitamin transfer to the conceptus and the alterations in yolk sac function associated with birth defects and diminished growth can be integrally related.

Animals↗

PubMedDate not supplied

Effects of zidovudine (AZT) and dideoxyinosine (ddI) on human trophoblast cells.

The anti-HIV agents AZT (zidovudine) and ddl (dideoxyinosine) are being used clinically during pregnancy. The toxicity of these agents to the fetus and placenta remains a concern because few human pregnancy exposure data are available, and pregnant rodent studies with AZT indicate increased embryonic resorptions and developmental arrest. The current study used a human choriocarcinoma cell line (JAr), which exhibits many characteristics of the early placenta, to assess the effects of a single 24 h exposure of 7.6 or 0.076 mM AZT, and the effects of a single 24 h exposure of 7.6 or 0.076 mM ddI upon cell proliferation and hormone production of human chorionic gonadotropin (hCG), estradiol (E2), and progesterone (P4). The higher concentration of AZT and ddI produced significant (P < 0.025) reductions in cell numbers and growth rate while producing significant increases in hormone production (hCG, E2, and P4). The lower concentration of AZT and ddI produced significant increases in E2 production, but no changes in cell numbers, hCG, or P4. Because placental cells require androgen precursor for E2 synthesis, exogenous androstenedione was added to confirm observations of increased estradiol synthesis after AZT or ddl exposure. These results demonstrate that single 24 h high dose exposures of AZT or ddI produce significant inhibition of cell proliferation and alterations in hormone production in this paradigm of human placental cells.

Androstenedione↗

PubMedDate not supplied

Post-implantation differentiation and proliferation of cytotrophoblast cells: in vitro models--a review.

Cytotrophoblast cells, specialized placental cells, proliferate early in pregnancy and then differentiate into tumour-like cells that invade the uterus and its vasculature. We have established in vitro models of three-dimensional cultures for anchoring villi and cell islands on extracellular matrix in order to study regulation of cytotrophoblast cell differentiation and proliferation. It has been demonstrated that cytotrophoblast cells from cell islands and cell columns share the same characteristics and that their differentiation is triggered by interaction with the extracellular matrix. The fact that during much of the first trimester maternal blood flow to the placenta is at a minimum, suggests that oxygen tension might regulate cytotrophoblast proliferation and differentiation. Hypoxia, comparable to that encountered by early gestation cytotrophoblast cells in the intervillous space, stimulated the cells to enter the cell cycle and inhibited their differentiation along the invasive pathway. Thus, oxygen gradient and cell-matrix interactions at the maternal-fetal interface play an important role in the regulation of cytotrophoblast proliferation and differentiation.

Cell Culture Techniques↗

PubMedDate not supplied

Normal characteristics of the Baumann (humerocapitellar) angle: an aid in assessment of supracondylar fractures.

We evaluated the normal Baumann (humerocapitellar) angle in 114 children aged 2-13 years because the angle has been proposed to be useful in assessing alignment of the elbow in children with supracondylar fractures of the humerus. In this age range, the angle did not change significantly, nor was there any significant difference between the angle in boys and girls. The mean Baumann angle was 72 degrees (SD 4 degrees), and 95% of normal elbows had a Baumann angle of 64 degrees-81 degrees.

Age Factors↗

PubMedDate not supplied

Prenatal diazepam exposure in rats: long-lasting functional changes in the offspring.

Adult (90-100 day-old) rats exposed prenatally (13-20 days of gestation) to diazepam (DZ) at 1.0, 2.5, or 10 mg/kg/day, were examined for functional deficits. Tests were designed to (1) correlate with known neural alterations induced by the prenatal exposure, or (2) to address the problem of developing tests of functional teratology in animals which have relevance to complex human functions. The careful selection of functional tests has disclosed several effects of prenatal DZ exposure on adult rat progeny. The dose-effect relationship was found to vary with the different tests, indicating that a thorough evaluation of the consequences of prenatal drug exposure necessitates utilization of several functional approaches. The results of these studies on the effects of prenatal exposure to DZ support the hypothesis that in utero exposure to drugs targeted for action on the central nervous system can induce long-lasting alterations on the neural substrates of behavior on the offspring with resulting functional consequences.

Animals↗