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E M Faustman

Publications and source records attributed to E M Faustman.

65 records · Page 4Linked to original sources
PubMed1989

Characterization of a developmental toxicity dose-response model.

The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included developmental evaluations of ethylene glycol, diethylhexyl phthalate, di- and triethylene glycol dimethyl ethers, and nitrofen in rats, mice, or rabbits. Graphic examination and statistical evaluation demonstrate that this model is sensitive to the data when compared to directly measured experimental outcomes. The model was used to interpolate to low-risk dose levels, and comparisons were made between the values obtained and the no-observed-adverse-effect levels (NOAELs) divided by an uncertainty factor. Our investigation suggests that the Rai and Van Ryzin model is sensitive to the developmental toxicity end points, prenatal deaths, and malformations, and appears to model closely their relationship to dose.

Abnormalities, Drug-Induced↗
PubMed1988

Developmental toxicity of aflatoxin B1 in the rodent embryo in vitro: contribution of exogenous biotransformation systems to toxicity.

Aflatoxin B1 (AFB1) is a known carcinogen and developmental toxin in various species of mammals, birds, amphibians, and fish. AFB1 requires metabolic activation (biotransformation) to the 2,3-epoxide metabolite for carcinogenicity; however, it is unknown if biotransformation is a prerequisite for AFB1 embryotoxicity. Cultured day 10 rat embryos were exposed to AFB1 alone and AFB1 in the presence of cofactors and hepatic S9 fractions from adult male rats induced with either phenobarbital or 3-methylcholanthrene. Under these different culture conditions qualitatively similar patterns of malformation were seen in all embryos exposed to AFB1. At culture concentrations of 15 microM or greater, AFB1 produced abnormalities in neural tube development in a concentration-dependent manner. The presence of hepatic S9 fractions had no effect on the ability of AFB1 to produce dysmorphogenesis in vitro or on the spectrum of malformations elicited. However, the addition of hepatic S9 fractions did greatly enhance the embryolethality of AFB1. This enhancement was greater with phenobarbital- than 3-methylcholanthrene-preinduced hepatic S9 fractions. Our results suggest that separate chemical mediators may be responsible for the embryolethal and dysmorphogenic effects of AFB1 observed in day 10 rat embryos in vitro. We found that the embryolethality of AFB1, but not the dysmorphogenicity, could be greatly modulated by exogenous biotransformation.

Abnormalities, Drug-Induced↗
PubMed1980

A method for the rapid quantitation of methylated hepatic DNA-purines using high pressure liquid chromatography.

An isocratic high pressure liquid chromatography system that can be employed for the separation and quantitation of four of the major methylated purines commonly found in DNA after exposure to carcinogenic/mutagenic alkylating agents (1-methyladenine, 3-methyladenine, O6-methylguanine and 7-methylguanine) is presented in this paper. Data from experiments in which rats were treated with methyl-N-nitrosourea have been used to illustrate the applicability of the method. The amounts of the methylated bases observed were consistent with values reported in the literature.

Alkylating Agents↗
PubMedDate not supplied

Expression of developmentally relevant proteins by rodent embryo CNS cells in vivo and in vitro: proto-oncogene pp60c-src and high molecular weight neurofilament protein.

The expression of proteins that play a role in neuronal differentiation was examined in central nervous system (CNS) micromass embryo cell cultures and compared to expression at comparable developmental stages in vivo. The protein product of the src proto-oncogene (pp60c-src) has been postulated to have a specific role in development because, although it is expressed in many tissues, marked increases in amount and activity of pp60c-src occur in neurons at the time of differentiation. Another protein of interest, high molecular weight neurofilament (NF) protein, is found in differentiated neurons. In the present study, changes over time in the expression of these two proteins in vitro and in vivo were examined. In the micromass cell cultures, primary cells from day 12 rat embryo CNS are plated at high density and differentiate into neurons during five days in culture. Tissues from embryos grown in vivo were assessed at 12 and 17 days post-coitum. Proteins were quantified by PAGE separation of equal amounts of total protein followed by transfer to membranes, immunoblotting, and densitometric scanning of blots. Increases in the amount of both proteins with neuronal differentiation was shown. Protein kinase activity of immunoprecipitated pp60c-src also increased in cell cultures and in embryos. Similarity in patterns of expression between in vitro and in vivo tissue samples provides further evidence that the cultures closely simulate in vivo differentiation and are a useful system for examining expression of developmental genes in vitro.

Animals↗
PubMedDate not supplied

Characterization of cytoskeletal and neuronal markers in micromass cultures of rat embryonic midbrain cells.

Micromass cultures of rat embryonic midbrain cells were characterized with regard to the immunolocalization of neuronal and cytoskeletal markers. Cells taken from gestational day-12 embryos and cultured for 5 days in vitro comprise at least two morphologically distinct cells types: fibroblast-like cells and neurons. Antibodies to the following markers yielded preferential staining of neuronal cells: A2B5 (GQ ganglioside), gamma-aminobutyric acid (GABA), microtubule-associated protein 2 (MAP2), MAP5, neuron-specific enolase (NSE), neural cell adhesion molecule (N-CAM), and tau. Antibodies to beta-tubulin, c-neu, MAP1, and neurofilament (NF-H) stained both neuronal and fibroblast-like cells. Antibodies to glial fibrillary acidic protein (GFAP) and vimentin failed to immunoreact with any cells in day-5 CNS cultures. SDS-PAGE and Western analysis were employed to determine the specificity of the antibodies and determine the electrophoretic profiles of the markers. We conclude that the pattern of neuronal differentiation in CNS micromass cultures exhibits certain similarities to that observed in vivo. In addition, certain markers identified in this study may be of potential utility as (1) biomarkers of chemically-induced developmental neurotoxicity, and (2) indicators of differential toxicity toward the diverse cell types that comprise the mammalian central nervous system.

Animals↗
PubMedDate not supplied

Gonadotropin regulation of glutathione synthesis in the rat ovary.

Glutathione (GSH), an antioxidant and conjugator of electrophilic toxicants, prevents toxicant-mediated destruction of ovarian follicles and oocytes. Ovarian GSH has previously been shown to change with estrous cycle stage in rats, suggesting that the gonadotropin hormones may regulate ovarian GSH synthesis. The present studies tested the hypotheses that [1] estrous cycle-related changes in ovarian GSH result from cyclic changes in protein and mRNA expression of the rate-limiting enzyme in GSH synthesis, glutamate cysteine ligase (GCL, also called gamma-glutamylcysteine synthetase), and [2] that these changes result from gonadotropin-mediated regulation of GCL subunit expression. In the first experiment, ovaries were harvested from cycling adult female rats on each stage of the estrous cycle. In the second experiment immature female rats were injected with pregnant mare's serum gonadotropin (PMSG) to stimulate follicular development or with vehicle and killed 8, 24, or 48 h later. In both experiments the ovaries were harvested for [1] total GSH assay, [2] Western analysis for GCL catalytic (GCLc) and regulatory (GCLm) subunit protein levels, or [3] Northern analysis for Gclc and Gclm mRNA levels. Ovarian GSH concentrations and Gclc and Gclm mRNA levels, but not GCL subunit protein levels, varied significantly with estrous cycle stage. PMSG administration significantly increased ovarian GSH concentrations 24 and 48 h later. GCLm protein levels increased significantly at 24 h and 48 h following PMSG. GCLc protein levels did not increase significantly following PMSG. Gcl subunit mRNA levels were not significantly increased at any time point by the planned ANOVA; however, an increase in Gelc at 48 h was identified by t-testing. These results support the hypothesis that gonadotropins regulate ovarian GSH synthesis by modulating GCL subunit expression.

Animals↗
PubMedDate not supplied

Weighing the risks and the benefits: a call for the empirical assessment of perceived teratogenic risk.

Pregnant women are often faced with complex decisions about whether to undergo medical treatment or continue working in an occupational setting that is permeated with hazardous chemicals. The task for these women is to weigh the benefits of these activities against the potential risks that they may have on the developing embryo. Scientific uncertainty with respect to the teratogenicity of drugs and chemicals in humans leaves health care professionals and their pregnant patients with little predictive information. Cognitive research has shown that it is difficult for people to make complex decisions, particularly when the risks are uncertain. Although the problems inherent in counseling pregnant women regarding teratogenic risk are not new, little time has been devoted to the empiric assessment of how people perceive teratogenic risk and how teratogenic risk information can be best communicated. This article explores the variables that have been found, through psychometric research, to influence people's perception of risk and how cognitive models derived from these studies may be applicable to teratogen information counseling. Understanding the variables that shape the perception of teratogenic risk can help health care professionals improve how they communicate these risks to their patients. Improved teratogenic risk communication will result in better management of pregnancies and reduction of costly litigation that ensues when risks are not properly communicated and understood.

Congenital Abnormalities↗
PubMedDate not supplied

Trichloroethylene: toxicology and health hazards.

Trichloroethylene (TCE), a synthetic compound widely used in many occupational and non-occupational settings, is one of the leading environmental contaminants. In this paper, current information on sources, human exposure, metabolism, toxicology and health impact of TCE is reviewed. The central nervous system is the major target for TCE toxicity. This compound, however, can also exert toxic effects on other tissues and organs, for example the myocardium, the kidney and the liver. Several rodent bioassays indicate that TCE is a carcinogen for laboratory animals. Human carcinogenicity, however, is still controversial as there are limited epidemiological studies available for assessment and important species differences in metabolism that make extrapolation from animal studies more challenging. Current regulatory standards are discussed in connection with the analysis of technical and medical prevention.

Animals↗