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Biomedical subjects

G P Daston

Publications and source records attributed to G P Daston.

At least 19 recordsLinked to original sources
PubMed2005

A safety assessment of coumarin taking into account species-specificity of toxicokinetics.

Coumarin (1,2-benzopyrone) is a naturally occurring fragrant compound found in a variety of plants and spices. Exposure to the general public is through the diet and from its use as a perfume raw material in personal care products. High doses of coumarin by the oral route are known to be associated with liver toxicity in rodents. Chronic oral bioassays conducted in the 1990s reported liver tumors in rats and mice and lung tumors in mice, raising concerns regarding the safety of coumarin. Since then, an extensive body of research has focused on understanding the etiology of these tumors. The data support a conclusion that coumarin is not DNA-reactive and that the induction of tumors at high doses in rodents is attributed to cytotoxicity and regenerative hyperplasia. The species-specific target organ toxicity is shown to be related to the pharmacokinetics of coumarin metabolism, with data showing rats to be particularly susceptible to liver effects and mice to be particularly susceptible to lung effects. A quantitative human health risk assessment that integrates both cancer and non-cancer effects is presented, confirming the safety of coumarin exposure from natural dietary sources as well as from its use as a perfume in personal care products.

Animals↗
PubMed2004

Cardiac abnormalities induced by zinc deficiency are associated with alterations in the expression of genes regulated by the zinc-finger transcription factor GATA-4.

Zinc (Zn) deficiency during pregnancy results in a wide variety of developmental abnormalities. The objective of this study was to determine if expression of cardiac developmental genes regulated by Zn-finger transcription factors could be modulated during dietary Zn deficiency. Rats were fed 0.5 (low Zn) or 90 (controls) microg Zn/g diet throughout pregnancy. Fetal development was examined and RNA isolated at gestation day (GD) 13 and 20. Cardiac abnormalities were detected at GD 20 in 82% of fetuses from dams fed low Zn diets compared with only 2% in controls. Cardiac developmental gene expression regulated by the Zn-finger transcription factor, GATA-4, was measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). In GD 13 and 20 hearts, two genes critical for heart development, alpha-myosin heavy chain (alpha-MHC) and cardiac troponin I (cTnI), were down-regulated in Zn-deficient fetuses. Expression of alpha-MHC was 66 and 40% lower at GD 13 and 20, respectively, in fetuses from dams fed low Zn diets compared with fetuses from control dams (p<0.05). Fetal cardiac TnI RNA levels were reduced 40 and 45% at GD 13 and 20 in the Zn-deficient group compared with controls (p<0.05). Fetal cardiac transcript levels of GATA-4 and MHox, a gene regulated by a helix-loop-helix transcription factor, whose expressions are not Zn-dependent, were unaffected by diet. These data indicated that alterations in gene regulation might be an underlying mechanism of cardiac abnormalities. Dysfunction of other Zn-dependent transcription factors may be an integral part of the extensive teratogenesis associated with Zn deficiency.

Abnormalities, Multiple↗
PubMed2001

A decrease in intracellular zinc level precedes the detection of early indicators of apoptosis in HL-60 cells.

Low extracellular zinc concentrations have been associated with the induction of apoptosis. To assess the relationship between intracellular zinc concentration and the rate of apoptosis, cells were grown in media containing 0.5, 25, or 50 microM zinc and analyzed by flow cytometry or fluorescence microscopy. Cells grown in 0.5 microM zinc medium over 48 h showed a successive decrease in intracellular zinc concentration measured by the zinc-specific fluorophore, zinquin. After 18 h in 0.5 microM zinc medium, rhodamine 123 retention decreased. However, the addition of 10 microM zinc to the 0.5 microM medium before 16 h in culture restored rhodamine retention in the cells. After 30 h there was an increase in the number of cells cultured in 0.5 microM zinc medium that bound annexin V-FITC. These data indicated that decreased intracellular zinc concentration preceded early markers of apoptosis, with alterations in mitochondrial transmembrane potential preceding the loss of polarity in the cell membrane.

Annexin A5↗
PubMed2000

Zinc-deficient rat embryos have increased caspase 3-like activity and apoptosis.

Caspase activity is a hallmark of apoptosis. Given that maternal zinc (Zn) deficiency results in apoptosis in the rat embryo, we assessed caspase activity in Zn-deficient embryos. Mid-gestation rat embryos were collected from dams fed either a Zn-deficient (0.5 Zn/g) diet ad libitum, or a Zn-adequate (25 microg Zn/g) diet ad libitum or pair fed to dams fed the Zn-deficient diet. Embryos from dams fed the Zn-adequate diet had a normal level of cell death, while embryos from the dams fed the Zn-deficient diet had either increased or normal levels of cell death. Zn-deficient embryos displaying increased cell death had increased caspase activity. Embryos with normal levels of cell death, regardless of maternal diet, had similar caspase activities. Thus, Zn-deficiency-induced apoptosis in vivo is associated with increased caspase activity.

Animals↗
PubMed1999

Evaluating the effects of endocrine disruptors on endocrine function during development.

The major concerns with endocrine disruptors in the environment are based mostly on effects that have been observed on the developing embryo and fetus. The focus of the present manuscript is on disruption of three hormonal systems: estrogens, androgens, and thyroid hormones. These three hormonal systems have been well characterized with regard to their roles in normal development, and their actions during development are known to be perturbed by endocrine-disrupting chemicals. During development, organs are especially sensitive to low concentrations of the sex steroids and thyroid hormones. Changes induced by exposure to these hormones during development are often irreversible, in contrast with the reversible changes induced by transient hormone exposure in the adult. Although it is known that there are differences in embryonic/fetal/neonatal versus adult endocrine responses, minimal experimental information is available to aid in characterizing the risk of endocrine disruptors with regard to a number of issues. Issues discussed here include the hypothesis of greater sensitivity of embryos/fetuses to endocrine disruptors, irreversible consequences of exposure before maturation of homeostatic systems and during periods of genetic imprinting, and quantitative information related to the shape of the dose-response curve for specific developmental phenomena.

Adult↗
PubMed1998

Rat embryos cultured under copper-deficient conditions develop abnormally and are characterized by an impaired oxidant defense system.

Rat embryos (gestation days 9.0 and 10.0) obtained from dams that were fed a Cu-adequate (8 micrograms Cu/g) or Cu-deficient (< 0.5 micrograms Cu/g diet were cultured for 48 hr in Cu-adequate (16.2 microM) or Cu-deficient (1.0 microM) rat serum. Control embryos cultured in control serum were morphologically normal. Embryos from Cu-deficient dams developed abnormally when cultured in Cu-deficient serum; the abnormalities included distended hindbrains, blisters, blood pooling, and cardiac defects. Control embryos cultured in Cu-deficient serum and Cu-deficient embryos cultured in control serum also showed abnormal development, but to a lesser degree than that of the Cu-deficient embryos cultured in Cu-deficient serum. To test the idea that the above abnormalities were due in part to free radical induced damage occurring secondary to an impaired oxidant defense system, a chemiluminescence assay was used to detect superoxide dismutase (SOD) activity in the cultured embryos. SOD activity was lowest in embryos cultured in Cu-deficient serum. When the Cu-deficient serum was supplemented with antioxidants (CuZnSOD or glutathione peroxidase), its teratogenicity was reduced. These data support the idea that an impaired oxidant defense system contributes to the dysmorphology associated with Cu deficiency. However, the Cu-deficient embryos also had low cytochrome c oxidase activity compared to control embryos--thus, multiple factors are likely contributing to Cu deficiency-induced abnormalities.

Adenosine Triphosphate↗
PubMed1998

Effect of copper deficiency on prenatal development and pregnancy outcome.

Copper deficiency during embryonic and fetal development can result in numerous gross structural and biochemical abnormalities. Such a deficiency can arise through a variety of mechanisms, including low maternal dietary copper intake, disease-induced or drug-induced changes in maternal and conceptus copper metabolism, or both. These issues are discussed in this article along with the use of in vitro embryo culture models to study the mechanisms underlying copper deficiency-induced teratogenesis. Current data suggest that changes in free radical defense mechanisms, connective tissue metabolism, and energy production can all contribute to the dysmorphogenesis associated with developmental copper deficiency.

Animals↗
PubMed1997

Repeated administration of alpha-hederin results in alterations in maternal zinc status and adverse developmental outcome in the rat.

The administration of alpha-hederin, an inducer of metallothionein, results in a secondary zinc deficiency that may be an important maternally mediated mechanism of developmental toxicity. Previous studies have shown adverse developmental outcome with a single administration of alpha-hederin to rats on gestation day (GD) 8 or 11. The objective of this study was to determine whether dosing of alpha-hederin throughout organogenesis would result in a sustained elevation of maternal hepatic metallothionein and subsequent developmental abnormalities. Rats were administered dosage levels of 0 (vehicle only), 20, or 30 mumol/kg from GD 6-15. Maternal hepatic metallothionein levels were 10-fold higher on GD 16 in the treatment groups than the controls. Consequently, liver zinc concentrations increased 60% and 54%, whereas plasma levels decreased 23% and 33% in the 20 and 30 mumol/kg treatment groups, respectively. At GD 20, mean fetal weights of the treatment litters were 11% less than control litters. The administration of alpha-hederin resulted in a threefold increase in the number of offspring that exhibited developmental abnormalities, including visceral and skeletal malformations. Following an oral pulse of 65Zn subsequent to treatment with 0 or 20 mumol/kg of alpha-hederin, the distribution of 65Zn to the liver of treated dams was twice that of controls, whereas the radiolabeled zinc apportioned to the decidua and uterus decreased by 44%. Furthermore, the 65Zn detected in the embryos from treated dams was 70% lower than in embryos from control dams. In conclusion, low doses of a metallothionein inducer administered to the dam from GD 6-15 resulted in a sustained elevation of hepatic metallothionein and a subsequent redistribution of zinc leading to a decrease in the zinc available to the embryo and ultimately to adverse development of the offspring. Repeated dosing throughout organogenesis, as required in regulated safety assessment testing, increased the severity of the effects previously observed with single large dosages of the toxicant administered during midgestation.

Animals↗
PubMed1996

The theoretical and empirical case for in vitro developmental toxicity screens, and potential applications.

In vitro assays for the screening of developmental toxicity potential have been under development for approximately 15 years. During that period, we have learned that assays consisting of primary cultures of embryonic tissues or cells, intact embryos in culture, or free-living embryos are capable of distinguishing between mammalian developmental toxicants and nondevelopmental toxicants with an accuracy of > or = 80%. Despite this level of performance, there is still considerable reluctance among the scientific community to employ these assays for preliminary screening. In this paper, I review the theoretical basis for the predictiveness of these assays, outline the empirical data indicating their utility in screening toxicants, discuss the major limitations of in vitro assays and how they can be managed, and suggest applications for in vitro pre-screens. The embryo-derived assays should work because they continue to develop in vitro, and the underlying cellular and molecular processes driving this development are the same as those in the mammalian embryo in situ, and therefore, susceptible to the same insults. The assays do work, as specific mechanisms of developmental toxicity have been demonstrated in vitro, and because extensive validation studies have shown them to be highly concordant with traditional in vivo screens. The assays are inherently limited by the fact that they do not include all the levels of complexity of the maternal-embryonic unit; however, these limitations can be minimized by thoughtful assay selection, study design, and interpretation. Potential applications are suggested that complement but do not replace in vivo testing. Pre-screens will make product development more efficient and add to our knowledge about the developmental toxicity of previously untested compounds. In vivo screening would still be conducted on all classes of substances that are currently tested for developmental toxicity; however, fewer chemicals with high likelihood of being developmentally toxic, and therefore not appropriate for further commercial consideration, would be evaluated in these costly screens.

Animals↗
PubMed1996

Endocrine modulation of reproduction.

The ability of foreign compounds to affect the functioning of various endocrine systems is currently thought responsible for a wide variety of effects. The presentations in this Symposium reviewed the evidence for and against the involvement of endocrine systems in several different aspects of reproduction. The mechanism behind the ability of a triazine herbicide to cause enhanced appearance of mammary tumors in one strain of female rats is reviewed by Stevens. The data suggest that enhanced aging, not direct mammary modulation, is responsible. Dietary phytoestrogens, the mediators of their actions, their effects in various biological systems, and the relationships between phytoestrogen producers and consumers are all provocatively and succinctly reviewed by Hughes. Kelce presents the strategy used to dissect the mode and mechanisms of action of a fungicide that opened a new awareness in reproductive toxicology: the possibility of xenobiotics being antiandrogens. Finally, to heighten our understanding of the interplay among hormonal systems in vivo, Hess reviews the data that show that androgens are not the only hormones important in the development of the male reproductive system: the pituitary is shown to play a critical role at specific stages of development. The breadth of these presentations, and the implications of their findings, should make us pause and realize how much there is still to discover about the interaction between the reproductive system and anthropogenic compounds.

Aging↗
PubMed1996

Benchmark dose analysis of developmental toxicity in rats exposed to boric acid.

Developmental toxicity risk assessment has typically relied on the estimation of reference doses or reference concentrations based on the use of no-observed-adverse-effect levels (NOAELs) divided by uncertainty factors. The benchmark dose (BMD) approach has been proposed as an alternative basis for reference value calculations. In this analysis of the developmental toxicity observed in rats exposed to boric acid in their diet, BMD analyses have been conducted using two existing studies. By considering various end points (rib XIII effects, variations of the first lumbar rib, and fetal weight changes) and various modeling approaches for those end points, the best approach for incorporating all of the information available from those studies could be determined. Particular emphasis has been placed on methods for combining data across studies and for combining potentially related effects (on rib XIII and on the first lumbar rib). The issues of study and end point selection are ones that will arise frequently in the process of estimating reference values. This example of boric acid suggests that the BMD approach provides a reasonable basis for appropriately comparing and combining study data, as opposed to ad hoc combinations of study results. Moreover, it is shown that the BMD approach can be used with combinations of end points considered to differ in severity. In this case, the preferred approach involved combining the data from the two studies, which were similarly designed and were conducted in the same laboratory, to calculate BMDs that were more accurate and more precise than those that could be derived from either study alone. It was determined that decreased fetal body weight provided the best basis for BMD calculations; BMDs calculated for fetal body weight changes were less than those for all other relevant end points. The appropriate BMD to use as the basis for boric acid reference dose calculation appears to be 59 mg/kg/day, which is very similar to the NOAEL observed in the second of the two studies (55 mg/kg/day). Although the first study failed to establish a NOAEL, the BMD approach could have been applied to that study, thereby avoiding the need for a repeat study. Similar BMD results were obtained in both studies.

Animals↗
PubMed1996

Maternal reproductive effects of oral salicylic acid in Sprague-Dawley rats.

Clinical and experimental evidence indicates that exposure to relative ly large doses of acetylsalicylic acid (ASA) prolongs parturition. However, little is known about the dose-response relationship for salicylate-related effects on labor and gestation. As well, the relative potency of salicylic acid (SA) as compared with ASA for these reproductive effects has not been well investigated. This study was designed to define a dose-response relationship for salicylic acid (SA) effects on labor and gestation times in Sprague-Dawley rats. Pregnant females received oral doses of 20,80, or 200 mg/kg/day sodium salicylate, or 260 mg/kg/day acetylsalicylic acid (ASA), as a positive control, on days 15 through 21 of gestation (sperm positive = day 0). Onset of labor was followed in each animal beginning on day 21 of gestation. The data failed to demonstrate a substantial potency difference between ASA and SA but some differences in toxicity were observed. Relative to controls, gestation times were unaffected by SA. SA treatment resulted in a dose-related trend towards increased duration of labor which was statistically significant at 200 mg/kg/day of SA. ASA treatment of pregnant females resulted in both prolonged labor and gestation times. Both the highest administered dose of SA and ASA treatment contributed to increased maternal peripartum death. Overall, the study confirms a dose-response relationship for SA-induced maternal reproductive effects and supports a no observable effect level (NOEL) for this compound of 80 mg/kg/day for adverse effects on parturition.

Administration, Oral↗
PubMed1996

Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop.

The hypothesis has been put forward that humans and wildlife species adverse suffered adverse health effects after exposure to endocrine-disrupting chemicals. Reported adverse effects include declines in populations, increases in cancers, and reduced reproductive function. The U.S. Environmental Protection Agency sponsored a workshop in April 1995 to bring together interested parties in an effort to identify research gaps related to this hypothesis and to establish priorities for future research activities. Approximately 90 invited participants were organized into work groups developed around the principal reported health effects-carcinogenesis, reproductive toxicity, neurotoxicity, and immunotoxicity-as well as along the risk assessment paradigm-hazard identification, dose-response assessment, exposure assessment, and risk characterization. Attention focused on both ecological and human health effects. In general, group felt that the hypothesis warranted a concerted research effort to evaluate its validity and that research should focus primarily on effects on development of reproductive capability, on improved exposure assessment, and on the effects of mixtures. This report summarizes the discussions of the work groups and details the recommendations for additional research.

Animals↗
PubMed1995

Zinc deficiency causes apoptosis but not cell cycle alterations in organogenesis-stage rat embryos: effect of varying duration of deficiency.

Zinc deficiency is teratogenic in all species in which it has been examined. Zinc is an essential component of enzymes involved in DNA synthesis and cell proliferation, and may play an as yet undetermined role in apoptosis. To further our understanding of the role of zinc in normal development, we examined cell death and cell cycle parameters in embryos of pregnant rats fed a zinc-deficient diet for 2 to 10 days (0.5 microgram zinc/g diet; zinc-adequate diet was 25 micrograms zinc/g). To elucidate sensitive periods of development and susceptible cell populations, dams were fed the zinc-deficient diet from gestation day 1, 3, 7, or 9 and killed on day 11. Embryos were examined for morphology and developmental stage. From each litter, 2-3 embryos were stained with Nile blue sulfate (NBS) to visualize cell death, 3 embryos were frozen for flow cytometric cell cycle analysis and cell counts, and selected embryos were preserved for histological examination. Dams fed the zinc-deficient diet for more than 3 days reduced their food intake through gestation day 8 but increased food intake on day 9. Maternal plasma zinc dropped to 10-25% of control levels in the zinc-deficient groups. Zinc deficiency from gestation day 1 or 3 resulted in two categories of affected litters on day 11. One category had embryos which were morphologically normal but displayed extensive NBS staining in the visceral arches, neural tube, and somites. The second category had developmentally retarded or maldeveloped embryos which showed little NBS staining. Zinc deficiency from gestation day 7 produced cell death in the posterior dorsal midline in the area of premigratory neural crest cells, which was confirmed by histological examination. Zinc deficiency from gestation day 9 did not affect morphology or NBS staining. Percentages of cells in the G0/G1, S, and G2M phases of the cell cycle on gestation day 11, determined by flow cytometry, were similar to controls in all groups. This study shows that as few as 4 days of maternal zinc deficiency can produce excess embryonal cell death, and that neural crest cells may be particularly sensitive.

Animals↗
PubMed1995

Evaluation of chick embryo neural retinal cell culture as a screen for developmental toxicants.

This paper describes a study to evaluate the concordance with in vivo results of an in vitro screen for developmental toxicants. The screen is a primary culture of chick embryo neural retina cells (CERC) which undergo processes of cell-cell recognition and interaction, growth, and differentiation over a 7-day culture period. Each of these developmentally significant events is measured separately as formation of multicellular aggregates, protein content, and glutamine synthetase activity, respectively. A total of 45 chemicals, 24 of which have been shown to be teratogenic at some dosage to mammalian embryos in utero, 7 of which are embryotoxic (but not teratogenic) in utero at high dosage, and 14 of which have not produced developmental toxicity in vivo, were evaluated in this assay by investigators who were blinded to the identity of the chemicals. Chemicals were tested up to concentrations that were frankly cytolethal, or up to a maximum of 5 mg/ml. Chemicals were present only during the first 24 hr of culture. The chemicals were selected to be representative of a variety of chemical classes (e.g., solvents, metals, food additives, anticonvulsants, antineoplastics). In several cases, pairs of structurally similar compounds with different developmental toxic potencies (e.g., valproate and 2-en-valproate, formamide, and N,N-dimethylformamide) were tested. Of the 31 developmental toxicants, 25 affected at least one endpoint in the assay at concentrations which are achievable in vivo (i.e., below the systemic concentration at a lethal dose), yielding a false-negative rate of 19%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Benchmark Dose Workshop: criteria for use of a benchmark dose to estimate a reference dose.

The purpose of the Benchmark Dose Workshop was to assess the feasibility and implications of replacing the no observed adverse effect level (NOAEL) with a benchmark dose (BMD) when deriving reference doses and concentrations (RfDs and RfCs). The workshop participants supported the use of the BMD method to remove many of the limitations inherent in using the NOAEL approach. Participants endorsed in general the use of a BMD for all quantal noncancer health effects and endorsed in particular the BMD for assessing developmental toxicity based on data presented at the workshop. The discussions of implementation recognized the need to demonstrate that changing from a NOAEL to a BMD gives the risk manager more certain information on which to base decisions. Most participants agreed that the current NOAEL-derived RfDs and RfCs are sufficiently protective and should only be changed as data become available for estimating a BMD. It was recognized that to achieve general acceptance of the BMD approach, it will have to be applied to a variety of endpoints.

Animals↗
PubMed1995

Tumor necrosis factor-alpha alters maternal and embryonic zinc metabolism and is developmentally toxic in mice.

We tested the hypothesis that tumor necrosis factor-alpha (TNF-alpha) would be teratogenic in mice due in part to its effects on zinc metabolism. In Experiment 1, nonpregnant mice were injected with a single dose of TNF-alpha (40,000 U) or PBS and then received a 65Zn-labeled meal. Mice killed 10 h after TNF-alpha treatment had high liver 65Zn and low plasma 65Zn, compared with controls. In Experiment 2, gestation day 8 (GD 8) mice were injected with PBS or TNF-alpha and then received a 65Zn-labeled meal. Dams killed 10 h after TNF-alpha treatment had higher liver and kidney 65Zn and lower plasma and embryonic 65Zn accumulation than controls. In Experiment 3, TNF-alpha dosing from GD 7-12 was associated with high maternal liver Zn and metallothionein concentrations on GD 13 and a high frequency of exencephaly on GD 18. In Experiment 4, dams fed diets containing 4.5, 12.5 or 50.0 micrograms Zn/g were given PBS or TNF-alpha on GD 7-12. Gross fetal defects were not observed in the PBS-treated litters evaluated on GD 18. In contrast, TNF-alpha-treated litters were characterized by multiple defects, with the incidence and severity being highest in the low Zn diet group. In Experiment 5, embryos cultured in serum from TNF-alpha-treated animals exhibited a high frequency of defects; the developmental toxicity of this serum was ameliorated when it was supplemented with Zn. Thus, the developmental toxicity of TNF-alpha is due in part to its influence on Zn metabolism.

Abnormalities, Drug-Induced↗