Teratogenicity of high vitamin A intake.
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Abnormalities, Drug-Induced↗
Biomedical subjects
R K Miller
Publications and source records attributed to R K Miller.
Energy charge monitoring via magnetic resonance spectroscopy 31P in the perfused human placenta: effects of cadmium, dinitrophenol and iodoacetate.
Phosphorus 31 nuclear magnetic resonance spectroscopy as a non-invasive technique was applied to monitor the metabolic activity of the human placenta during perfusion in vitro. During control perfusions (n = 3) there was an initial increase in adenosine triphosphate (ATP) and a fall in inorganic phosphate (Pi). Thereafter, however, the level of both ATP and Pi remained constant throughout the perfusion period (11 h). Additional biochemical parameters such as glucose consumption, lactate production and the release of hormones, human chorionic gonadotrophin (hGC). measured in the perfusate samples, were also used to assess the viability of the placental tissue. As with ATP, all these biochemical parameters under the control conditions showed a stable rate of metabolic activity throughout the length of the experiments. In additional experiments, the effect of the metabolic inhibitor dinitrophenol (n = 2) and dinitrophenol (DNP) together with iodoacetic acid (IOA, n = 2) were studied. DNP (0.1 mM) alone showed a slight decrease of all parameters. In contrast, the addition of IOA (0.1 mM) with DNP (0.1 mM) not only blocked the production of ATP but also produced a substantial impact on placental metabolic activity. The effect of a toxic dose of cadmium (20 nmol/ml) was studied also (n = 3). This dose of cadmium demonstrated no effect on phosphorus metabolism. However, the rate of glucose consumption and the release of hCG were significantly reduced.
Adenosine Triphosphate↗
Influence of realimentation of mature cows on maturity, color, collagen solubility, and sensory characteristics.
Cull beef cows (n = 80) that had consumed similar grassland diets were assigned to one of four feeding periods (0, 28, 56, and 84 d) and subdivided into two groups fed either a high-energy, high-protein diet or a high-energy, low-protein diet. Treatments were designed to examine the effect of time on feed, dietary protein, and electrical stimulation on carcass traits, composition, shear force, sensory profile, collagen characteristics, and myoglobin state. Within 1 h of slaughter, the right side of each carcass was electrically stimulated, and the left side served as the control. The only trait influenced by protein level was longissimus muscle area, for which a high-protein diet resulted in larger (P < .05) longissimus muscle areas. Increased time on a high-energy diet increased USDA yield grade and sensory ratings; however, metmyoglobin and reduced myoglobin values decreased between 0 and 28 d on feed. Electrical stimulation improved lean color, shear force values, and sensory attributes. Electrical stimulation decreased shear force by 2.8 kg for 0-d carcasses. With subsequent days on feed, shear force values continued to decrease, but this effect was minimal in electrically stimulated carcasses. However, protein level did not significantly influence palatability and quality attributes. The greatest (P < .05) improvement in marbling score was observed in electrically stimulated carcasses from cows fed for 84 d. Additionally, feeding a high-protein diet for 84 d resulted in a slightly lower maturity score. Even though values for palatability and quality traits were improved by antemortem and postmortem treatments, the magnitude of improvement may not be great enough for steaks from mature fed cows to be considered as acceptable as steaks from young fed beef.
Aging↗
Cellular adaptation to chronic cadmium exposure: intracellular localization of metallothionein protein in human trophoblast cells (JAr).
Trophoblast cells are the first embryonic cells that modulate the transfer of a variety of compounds (oxygen, amino acids, xenobiotics, metals) from the maternal to the fetal circulation in the human placenta. Human placental exposure to the toxic metal, cadmium (Cd) results in a decrease in the production of human chorionic gonadotropin (hCG), a decrease in the maternal to fetal transport of zinc (Zn), and trophoblastic necrosis. Thus, the ability of trophoblast cells to adapt to exposure to the toxic metal Cd has been considered crucial. In this study, the expression and intracellular localization of metallothionein (MT), a small molecular weight, metal binding protein, was examined in trophoblast cells (JAr) grown in normal media and in cells exposed chronically (6 months) to 2 microM CdCl2. Conventional and confocal fluorescence microscopy were used to examine the intracellular localization of MT protein in control cells and cells grown chronically in Cd. In unexposed trophoblast cells, MT protein was primarily perinuclear with low level, punctate expression in the cytosol. Following both chronic and 24 hour exposure to Cd, MT protein levels were increased (at least 3-fold in both chronic and acute exposures) and the protein was now concentrated inside the nucleus with a lacy, cytoskeletal pattern of expression in the cytosol. To determine if the nuclear accumulation of MT protein was dependent on new protein synthesis, control cells were exposed to CdCl2 (2 microM) and cycloheximide (2 micrograms/. ml) for 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Cadmium↗
Health risks associated with prenatal metal exposure.
A symposium entitled Health Risks Associated with Prenatal Metal Exposure was held at the 33rd Annual Meeting of the Society of Toxicology (SOT) in Dallas, Texas. The symposium was cosponsored by the Metals and Reproductive and Developmental Specialty Sections of SOT and was designed to elaborate the health risks associated with in utero exposure to metals commonly found in the workplace and/or ambient environment on the mother and developing offspring. Epidemiological and toxicological evidence that demonstrates the health effects and underlying mechanisms associated with exposure to arsenic (As), lead (Pb), and methyl mercury (MeHg) were discussed, as well as the legal ramifications and personal implications associated with prenatal metal exposure. The following is a summary of each of the individual presentations.
Animals↗
The effect of selenium compounds (selenite, selenate, ebselen) on the production of thromboxane and prostacyclin by the human term placenta in vitro.
Selenium not only has an important role in controlling lipid hydroperoxides through glutathione peroxidase (GPX) activity, but also can produce oxidative stress through exposure to selenite. Because levels of lipid hydroperoxides affect the production of thromboxane A2 (TxA2) and prostacyclin (PGI2), selenium compounds may be able to influence the production of these two vasoactive substances. Late-gestation pregnancy reduces the half-life of PGI2; therefore, pregnancy itself may enhance susceptibility to changes in the production of TxA2 and PGI2. The objective of this investigation was to determine if different selenium compounds, selenite, selenate, and ebselen, can influence the human term placental production of thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), the inactive hydrolysis products of TxA2 and PGI2. Although selenate exposure (40 microM 24 hr) increased TxB2 production, and ebselen (an organic selenium compound with GPX activity) exposure (40 microM, 24 hr) decreased both TxB2 and 6-keto-PGF1 alpha production, only selenite had a significant effect on the TxB2/6-keto-PGF1 alpha ratio. Three exposures to selenite at 6 microM (32 hr) significantly decreased 6-keto-PGF1 alpha production with no effect on TxB2 production or tissue GPX activity. Following two exposures to selenite at 20 and 40 microM (24 hr), TxB2 production was significantly increased, while tissue 6-keto-PGF1 alpha production and tissue GPX activity were significantly decreased. These results indicate that selenite, but not selenate or ebselen, can directly affect the human placenta by producing changes in the TxB2/6-keto-PGF1 alpha ratio, which may be related to increased vasoconstriction and blood coagulation.
Azoles↗
Cytomegalovirus in the perfused human term placenta in vitro.
Cytomegalovirus (CMV) is one of the most frequent causes of intrauterine-acquired infection in the human species. However, very little is known about the pathophysiology of the transplacental transmission of the virus from the mother to the fetus. In this study, the passage of CMV across the human term placenta, and the susceptibility of the human term trophoblast to infection with CMV was investigated. In vitro dual perfusion of human term placental lobules was performed. In five experiments the perfused tissue was exposed to high titres (10(4)-10(6) 50 per cent tissue culture infective doses) of CMV AD169 for up to 9.5 h. Monitoring included placental functional parameters, and virus titres in the perfused tissue, and in the fetal and maternal circuit. Immunocytochemistry with a monoclonal antibody against CMV immediate early antigen was used to search for placental infection. CMV AD169 did not cross the placenta even during many hours of perfusion, up to 9.5 h, and with exposure to high virus titres. No infected placental cells were detected by immunocytochemistry, although the virus cultures from perfused tissue samples were positive. The perfused human term placenta and the term trophoblast in vitro form an effective barrier to cell-free CMV AD169.
Cytomegalovirus↗
Continuous measurement of ATP by 31P-NMR in term human dually perfused placenta in vitro: response to ischemia.
ATP was examined in dually perfused term human placentas by using 31P-nuclear magnetic resonance (NMR) spectroscopy. 31P-NMR spectra were acquired every 30 min starting approximately 30 min after establishing fetal and maternal perfusions, and maternal perfusate samples were obtained to monitor glucose utilization, lactate production, and human chorionic gonadotropin (hCG) and human placental lactogen (hPL) release. In continuous-perfusion experiments, placentas were perfused as long as 10 h. ATP increased and Pi fell after initiation of perfusion. Fetal volume loss was < 2 ml/h, and constant production of hCG, hPL, and lactate as well as constant utilization of glucose were observed. In additional experiments, ischemia was produced by halting maternal and fetal perfusion pumps after a 2-h control period. After 2, 3, or 4 h of ischemia, ATP decreased 46 +/- 17, 51 +/- 5, and 85% of control, respectively. When perfusion was reinitiated, ATP increased and was maintained for the duration of the experiment (an additional 2 h). Recovery of ATP after reperfusion was not paralleled by recovery in glucose utilization, lactate production, or hPL and hCG release. However, during the reperfusion period, fetal pressure was < 70 mmHg and fetal volume loss was < 2 ml/h. These investigations suggest that the dually perfused human placental lobule can maintain ATP for > or = 10 h. Although the perfused human placenta recovers ATP and maintains fetal perfusion volume after ischemia lasting up to 4 h, utilization of glucose, production of lactate, and production and release of hCG and hPL are impaired.
Adenosine Triphosphate↗
Ostrich slaughter and fabrication: 1. Slaughter yields of carcasses and effects of electrical stimulation on post-mortem pH.
A commercial ostrich slaughter protocol was developed. Ostriches (n = 7 males and n = 7 females) averaged 95.54 kg live weight and yielded 55.91-kg carcasses. By-product yields were measured. The most significant by-products by weight were full viscera (8.29 kg), hide (6.71 kg), full gizzard and crop (5.80 kg), and abdominal fat (4.11 kg). Sex had no effect on slaughter yields. Post-mortem temperature declines were measured on five separate muscles and showed that chilling for 24 h was sufficient to adequately chill the deep muscle temperature to under 4 C. The effect of electrical stimulation on post-mortem pH decline also was investigated and had no effect.
Animals↗
Female reproductive and developmental toxicology: overview and current approaches.
In recent years, concern about possible female reproductive and developmental toxicity due to environmental contaminants, such as PCBs, has been growing. Because this area of toxicology had not been emphasized prior to this time, there are many gaps in current knowledge about female developmental and reproductive toxicology and only a limited number of validated tests to assay effects of toxicants on various parts of the reproductive and developmental cycle. This article reviews the current state of knowledge on this topic and also explores a variety of techniques for assessing female reproductive and developmental toxicity. These include an assay of the state of intercellular communication among the embryo, fetus and placenta; protocols for assessing toxicity in early pregnancy; and techniques for evaluating the role of glutathione in protecting the conceptus from xenobiotics.
Embryonic and Fetal Development↗
The placental transfer and toxicity of selenite relative to cadmium in the human term perfused placenta.
Selenite and cadmium both cause reproductive effects in animals. Cadmium is an acute placental toxicant, with apparent limited transfer to the fetus. This study examines the placental transfer of selenite, and the hypothesis that similar to cadmium, selenite may also be a direct placental toxicant. Using dual perfusion of the human term placental lobule, both non-protein bound (< 776 Da) selenite and cadmium equilibrated across the placenta within 4 h. The transfer of selenium, added as selenite, was not limited at concentrations from 2-40 nmol/ml. At initial maternal concentrations of 20 nmol/ml, selenium attained higher concentrations in the fetal perfusate compared with cadmium concentrations. Protein binding of cadmium in perfusates (45 per cent at 30 min) and placental cytosol (approx. 87 per cent) was greater than selenium (perfusate, 7 per cent at 30 min, cytosol, 50-60 per cent), which may partially account for the differences in placental transfer. Cadmium (20 nmol/ml) produced adverse effects on the production and release of human chorionic gonadotropin (hCG) in 4 h. No adverse effects were noted during 4 h exposures to selenite at initial concentrations of up to 40 nmol/ml. Thus, unlike cadmium, in which placental accumulation and direct placental toxicity contributed to acute reproductive effects, selenite at concentrations up to 40 nmol/ml was not a direct toxicant under these perfusion conditions.
Cadmium↗
Human placenta makes extracellular glutathione peroxidase and secretes it into maternal circulation.
Extracellular glutathione peroxidase (eGPX) is a selenoglycoprotein distinct from cellular glutathione peroxidase (cGPX). The cDNA for eGPX has recently been cloned from human placenta. To determine whether human placenta makes both cGPX and eGPX and secretes eGPX, we used specific immunoprecipitations of 75Se metabolically labeled proteins from full-term placental explants in culture and perfused placental lobules. Placental explants and metabolically active, dually perfused placental lobules synthesized and contained both cGPX and eGPX and secreted eGPX. Perfused tissue secreted eGPX into the maternal but not into the fetal perfusate. In situ hybridizations using antisense and sense eGPX riboprobes were performed on sections of first-, second-, and third-trimester placentas. In the first-trimester placenta, transcripts were localized predominantly to cytotrophoblast cells, whereas in the full-term placenta syncytiotrophoblast cells and stromal cells but not fetal endothelial cells expressed eGPX mRNA. It is concluded that human placenta synthesizes both cGPX and eGPX and secretes eGPX into the maternal circulation, consistent with the location of the eGPX mRNA.
Culture Techniques↗
Predicting intramuscular fat in beef longissimus muscle from speed of sound.
The ultrasonic A-mode method was investigated for intramuscular fat measurement of beef. Cubes of meat samples that had different marbling scores were used as specimens. Ultrasonic speed decreased with increasing fat concentration. The correlation coefficient was -.82 (P < .05). Conversely, the correlation coefficient between visual marbling score and fat concentration was .70 (P < .05). Quantitatively, from the first derivative of a nonlinear function, it was concluded that the speed decreased at a rate of 2.69 m/(s-% fat) as a function of intramuscular fat. A nonlinear regression model to predict intramuscular fat content in beef was developed as follows: percentage of fat concentration = 7132.1574-9.1222 x (speed) + 2.91803 x 10(-3) x (speed)2 (R2 = .81). The nonlinear model was capable of predicting intramuscular fat concentration with 90% accuracy (> 8% fat) and 76.4% accuracy (< 8% fat), respectively (P < .001).
Adipose Tissue↗
Measuring intramuscular fat in beef with ultrasonic frequency analysis.
Frequency analysis of Fourier spectra from ultrasonic signals was used for predicting intramuscular fat content of beef tissue. The most significant parameter in the frequency domain for predicting intramuscular fat concentration in beef was the number of local maxima. It represents the discontinuity of the Fourier spectrum caused by inhomogeneous fat concentrations in the longissimus muscle, which had the correlation coefficient .89 (P < .05) when a 2.25-MHz shear probe was used. The optimum frequency for predicting the amount of intramuscular fat content in the longissimus muscle was found to be 1.92 MHz. A multivariate regression model was developed using parameters in the frequency domain as follows: percentage of fat concentration = 1.790 - 2.373x (lower frequency) + .049x (bandwidth) + 1.178x (local maxima) (R2 = .82). Validation demonstrated that the multivariate model in the frequency domain was capable of predicting intramuscular fat concentration with an average of 1.17 percentage of fat error (P < .05). The multivariate model was most appropriate for predicting intramuscular fat below 4%. The mean accuracy of the model in the frequency domain was approximately 79%.
Adipose Tissue↗
The role of the human placenta in embryonic nutrition. Impact of environmental and social factors.
The human placenta has been implicated in the poor growth and development of the embryo/fetus due to alterations in blood flow and reductions in the transfer of nutrients such as amino acids and carbohydrates. Deficiencies of such nutrients have been the principal of many research investigations. The role of micronutrients, however, may also be major factors in appropriate growth and development, and there may be a general reduction in the availability of such nutrients, for example, the role of folate supplementation during early pregnancy and the reduction in the incidence of neural tube defects. Vitamins are not all transported via a common mechanism. Therefore, the modulation of human placental transport can be different for different vitamins, for example, A and B12. It is apparent that the human placenta can oxidatively metabolize retinoids (isotretinoin and tretinoin) to more toxic or less toxic metabolites. These metabolites can then be transferred to the fetal circulation. Such metabolism/transfer is in contrast to how vitamin B12 is bound to transcobalamin proteins, which are produced by the placenta and directionally released into the maternal and fetal circulations.
Embryonic and Fetal Development↗
Human trophoblast cultures: models for implantation and peri-implantation toxicology.
Implantation is the process that leads from blastocyst attachment to its embedding in the uterine wall. It is widely believed that failure of implantation is a common cause of pregnancy loss. Toxic agents can interfere directly with the process of implantation and therefore may account for unexplained implantation failures. Our knowledge of human implantation remains limited, mainly due to the lack of adequate experimental models. Studies of mechanisms underlying implantation in humans are by nature and for ethical reasons restricted to in vitro models. The aim of this review is to provide a critical evaluation of various in vitro models of implantation in humans, as well as essential background knowledge required for application of these models to the assessment of peri-implantation toxicity. Particular attention has been devoted to cell-cell and cell-matrix interactions as possible endpoints in the screening of toxic agents.
Animals↗
Dynamics of keratin assembly: exogenous type I keratin rapidly associates with type II keratin in vivo.
Keratin intermediate filaments (IF) are obligate heteropolymers containing equal amounts of type I and type II keratin. We have previously shown that microinjected biotinylated type I keratin is rapidly incorporated into endogenous bundles of keratin IF (tonofilaments) of PtK2 cells. In this study we show that the earliest steps in the assembly of keratin subunits into tonofilaments involve the extremely rapid formation of discrete aggregates of microinjected keratin. These are seen as fluorescent spots containing both type I and type II keratins within 1 min post-injection as determined by double label immunofluorescence. These observations suggest that endogenous type II keratin subunits can be rapidly mobilized from their endogenous state to form complexes with the injected type I protein. Furthermore, confocal microscopy and immunogold electron microscopy suggest that the type I-type II keratin spots from in close association with the endogenous keratin IF network. When the biotinylated protein is injected at concentrations of 0.3-0.5 mg/ml, the organization of the endogenous network of tonofilaments remains undisturbed during incorporation into tonofilaments. However, microinjection of 1.5-2.0 mg/ml of biotinylated type I results in significant alterations in the organization and assembly state of the endogenous keratin IF network soon after microinjection. The results of this study are consistent with the existence of a state of equilibrium between keratin subunits and polymerized keratin IF in epithelial cells, and provide further proof that IF are dynamic elements of the cytoskeleton of mammalian cells.
Animals↗
Progesterone antagonist mifepristone (RU 486) decreases cardiotoxicity of cocaine.
RU 486, a potent progesterone antagonist, was used to determine whether RU 486 blocks the enhanced cardiotoxicity of cocaine mediated by progesterone upon rat papillary muscles. Groups of nonpregnant rats were pretreated with: progesterone for 3 days (n = 12); progesterone + RU 486 for 3 days (n = 12); progesterone for 3 days + single low dose RU 486, progesterone for 3 days + single high dose RU 486, and RU 486 for 3 days (n = 6); or were untreated (n = 12). Papillary muscles from these groups were electrically paced during exposure to cocaine concentrations ranging from 10(-14) M to 10(-3) M. One group (n = 6) was pretreated with RU 486, but not exposed to cocaine. The results showed that all muscles from rats pretreated with RU 486 for 3 days were functional when exposed to cocaine concentrations one to four orders of magnitude higher than tolerated by muscles from untreated or progesterone-treated rats. As indicated by alterations in contraction response patterns, RU 486 treatment for 3 days reversed progesterone-enhanced cardiotoxicity of cocaine. Single low dose and high dose RU 486 administrations also reversed progesterone's effects upon cocaine-induced cardiotoxicity.
Analysis of Variance↗