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Biomedical subjects

J D Groopman

Publications and source records attributed to J D Groopman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Predictive value of molecular dosimetry: individual versus group effects of oltipraz on aflatoxin-albumin adducts and risk of liver cancer.

Studies in animals and humans have established serum aflatoxin-albumin adducts as biomarkers of exposure to aflatoxin B1 (AFB1), a food-borne hepatocarcinogen. To assess the utility of measurements of aflatoxin-albumin adducts to predict risk of hepatocellular carcinoma (HCC), 123 male F344 rats were dosed with 20 microg of AFB1 daily for 5 weeks after randomization into three groups: no intervention; delayed-transient (500 ppm of oltipraz, weeks 2 and 3 relative to AFB1); or persistent (500 ppm oltipraz, weeks -1 to 5). Serial blood samples were collected from each animal at weekly intervals throughout aflatoxin B1 exposure and assayed for levels of aflatoxin-albumin by radioimmune assay. Area under the curve (AUC) values for aflatoxin-albumin adducts decreased 20 and 39% in the delayed-transient and persistent oltipraz intervention groups, respectively, as compared to no intervention. Similarly, the total incidence of HCC dropped from 83 to 60% (P = 0.03) and 48% (P < 0.01) in these groups. Tumor multiplicity was also reduced in the two oltipraz intervention groups, whereas time to HCC was increased. Mononuclear cell leukemia, a common neoplasm in F344 rats, was seen in 39% of the control animals, whereas the two oltipraz interventions reduced incidence to 18% (P = 0.05) and 13% (P = 0.01), respectively. Overall, a significant association was seen between biomarker AUC and risk of HCC (P = 0.01). However, when the predictive value of aflatoxin-albumin adducts was assessed within treatment groups, there was no association between AUC and risk of HCC (P = 0.56). Thus, aflatoxin-albumin adducts can be useful for monitoring population-based changes induced by interventions, such as in chemoprevention trials, but have limited utility in identifying individuals destined to develop HCC. As a consequence, the use of this biomarker in quantitative risk assessment should be pursued cautiously.

Aflatoxin B1↗
PubMed1997

Oltipraz chemoprevention trial in Qidong, Jiangsu Province, People's Republic of China.

Oltipraz has been used clinically in many regions of the world as an antischistosomal agent and is an effective inhibitor of aflatoxin hepatocarcinogenesis in rats. This chemopreventive action of oltipraz results primarily from an altered balance in aflatoxin metabolic activation and detoxication. In 1995, a randomized, placebo-controlled, double-blind intervention was conducted in residents of Qidong, People's Republic of China, who are at high risk for exposure to aflatoxin and development of hepatocellular carcinoma. The major study objectives were to define a dose and schedule for oltipraz that would reduce levels of aflatoxin biomarkers in biofluids of the participants, and to further characterize dose-limiting side effects. Two hundred thirty-four healthy eligible individuals, including those infected with HBV, were randomized to receive either 125 mg oltipraz daily, 500 mg oltipraz weekly, or placebo. Blood and urine specimens were collected to monitor potential toxicities and evaluate biomarkers over the 8-week intervention and subsequent 8-week follow-up periods. Overall, compliance in the intervention was excellent; approximately 85% of the participants completed the study. Objective evaluation of adverse events was greatly facilitated by inclusion of a placebo arm in the study design. A syndrome involving numbness, tingling, and pain in the fingertips was the only event that occurred more frequently among the active groups (18 and 14% of the daily 125 mg and weekly 500 mg arms, respectively) compared to placebo (3%). These symptoms were reversible and could be relieved with non-steroidal antiinflammatory agents. A more complete understanding of the chemopreventive utility of oltipraz awaits completion of an assessment of the efficacy of oltipraz in modulating levels of aflatoxin biomarkers.

Animals↗
PubMed1996

Increased oxidative DNA damage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a more potent hepatocarcinogen in female than in male or ovariectomized rats. A possible mechanism for this increased sensitivity is through enhanced metabolic activation of estrogens by TCDD-induced enzymes leading to oxidative damage in the cell. As a marker for oxidative DNA damage, 8-oxo-deoxyguanosine (8-oxo-dG) was quantitated in livers of intact and ovariectomized Sprague-Dawley rats chronically treated with TCDD (125 ng/kg per day) with and without diethylnitrosamine as initiator. Elevated levels of 8-oxo-dG were detected in a significantly greater number of the intact compared to ovariectomized TCDD-treated rats. Expression of CYP1B1 mRNA, a newly identified cytochrome P450 with proposed estrogen hydroxylase activity, was highly induced by TCDD. The results are consistent with the hypothesis that increased metabolism of endogenous estrogens to catechols by TCDD-induced enzymes may lead to increased oxidative DNA damage and hence contribute to TCDD-mediated hepatocarcinogenicity in female rats.

Animals↗
PubMed1996

An aflatoxin-associated mutational hotspot at codon 249 in the p53 tumor suppressor gene occurs in hepatocellular carcinomas from Mexico.

The p53 tumor suppressor gene is commonly mutated in human hepatocellular carcinoma (HCC). The most frequent mutation in HCC in populations exposed to a high dietary intake of aflatoxin B1 (AFB1) is an AGGarg-->AGTser missense mutation in codon 249 of the p53 gene. We analyzed HCCs from Monterrey, Mexico, for the codon 249ser hotspot mutation. We also analyzed the serum AFB1-albumin adduct levels of the donors and family members to measure the current AFB1 exposure in this population. Moreover, the presence of hepatitis B and/or C viral infection (HBV or HCV) was analyzed serologically in the patients. Tumor cells were microdissected from tissue sections and exon 7 p53 sequences were amplified by polymerase chain reaction from genomic DNA and sequenced directly. The serological tests for anti-p53 antibodies, HBV or HCV were done by ELISA. Immunohistochemical analysis of p53 protein was done using a polyclonal rabbit antiserum (CM-1). Eight of 21 cases were positive by p53 immunohistochemistry. Of the 16 cases sequenced for exon 7 of p53 three codon 249 AGGarg-->AGTser mutations were found. Serum antibodies recognizing p53 protein were found in one of 18 patients. Positive serology for HBV and/or HCV was found in 12 of 20 cases. The serum AFB1-albumin adduct levels in this population ranged from 0.54 to 4.64 pmol aflatoxin/mg albumin. These results indicate that dietary AFB1 and hepatitis viruses are etiological agents in the molecular pathogenesis of HCC in this geographic region of Mexico.

Adult↗
PubMed1996

Inhibition of aflatoxin Ml excretion in rat urine during dietary intervention with oltipraz.

4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) is an effective chemopreventive agent against several classes of carcinogens in many target organs. Induction of carcinogen detoxication enzymes, particularly glutathione S-transferases, appears to be an important component of the protective actions of oltipraz. It has recently been observed that addition of oltipraz to rat liver microsomes or to cultured human hepatocytes blocks the oxidative metabolism of aflatoxin B1 (AFB1) to its 8,9-oxide and the hydroxylated derivative aflatoxin Ml (AFM1). 0ltipraz is a competitive and perhaps irreversible inhibitor of cytochromes P450 1A2 and 3A4. To determine whether oltipraz can affect cytochrome P450-dependent metabolism of AFB1 in vivo we have assessed the effect of oltipraz on the urinary excretion of oxidative metabolites of AFB1 before, during and after a transient intervention. Male F344 rats, housed individually in glass metabolism cages, were gavaged daily with 25 microg [3H]AFB1 for 28 consecutive days. Starting on day 6 and extending to day 16 half of the rats were fed a diet supplemented with 0.075% oltipraz. Sequential 24 h urine samples were collected and a subset analyzed for AFB1 metabolites. AFM1 was the major metabolite detected in all urine samples, accounting for 2-6% of the administered dose. The excretion of AFM1 was greatly reduced (77%) during the active phase of the intervention, when oltipraz was added to the diet, but rapidly returned to control levels after cessation of oltipraz administration. This inhibition of AFM1 excretion was not seen in animals receiving oltipraz by gavage 24 h prior to dosing with AFB1. Collectively these data are consistent with the view that oltipraz or a short-lived metabolite inhibits cytochrome P450 1A2 in vivo.

Aflatoxin B1↗
PubMed1996

Benzene exposure, assessed by urinary trans,trans-muconic acid, in urban children with elevated blood lead levels.

A pilot study was performed to evaluate the feasibility of using trans,trans-muconic acid (MA) as a biomarker of environmental benzene exposure. A secondary aim was to provide data on the extent of exposure to selected toxicants in a unique population consisting of inner-city children who were already overexposed to one urban hazard, lead. Potential sources of benzene were assessed by a questionnaire. Exposure biomarkers included urinary MA and cotinine and blood lead. Mean MA was 176.6 +/- 341.7 ng/mg creatinine in the 79 children who participated. A wide range of values was found with as many as 10.1%, depending on the comparison study, above the highest levels reported in adults not exposed by occupation. Mean MA was increased in children evaluated in the afternoon compared to morning, those at or above the median for time spent playing near the street, and those studied in the first half of the investigation. MA levels were not associated with blood lead or, consistently, with either questionnaire environmental tobacco smoke (ETS) data or cotinine. As expected, the mean blood lead level was elevated (23.6 micrograms/dl). Mean cotinine was also increased at 79.2 ng/mg creatinine. We conclude that the use of MA as a biomarker for environmental benzene exposure is feasible since it was detectable in 72% of subjects with a wide range of values present. In future studies, correlation of MA with personal air sampling in environmental exposure will be essential to fully interpret the significance of these findings. In addition, these inner-city children comprise a high risk group for exposure to environmental toxicants including ETS, lead, and probably benzene, based on questionnaire sources and its presence in ETS.

Benzene↗
PubMed1996

Molecular biomarkers for aflatoxins: from adducts to gene mutations to human liver cancer.

Over the past 30 years there have been extensive efforts to investigate the association between aflatoxin exposure and human liver cancer. These studies have been hindered by the lack of adequate dosimetry data on aflatoxin intake, excretion, and metabolism in people, as well as by the general poor quality of worldwide cancer morbidity and mortality statistics. These realities have spurred the efforts to develop new technologies to assess exposure status and risk for aflatoxins, and these agents are among the few environmental carcinogens for which quantitative risk assessments have been attempted. One of the goals of these risk assessments has been the development of primary and secondary preventive intervention methods to lower the human health impact from aflatoxin exposures. The long-term goal of the research described herein is the application of biomarkers to the development of preventive interventions for use in human populations at high risk for cancer. Several of the aflatoxin-specific biomarkers have been validated in epidemiologic studies and are now available for use as intermediate biomarkers in prevention trials. The development of these aflatoxin biomarkers has been based upon the knowledge of the biochemistry and toxicology of aflatoxins gleaned from both experimental and human studies. These biomarkers have been utilized subsequently in experimental models to provide data on the modulation of the markers under different situations of disease risk. This systematic approach provides encouragement for preventive interventions and should serve as a template for the development for the development and validation of other chemical-specific biomarkers and their application to cancer or other chronic diseases.

Aflatoxins↗
PubMed1996

Variability of molecular biomarker measurements from nonlinear calibration curves.

In any immunoassay experiment for the detection of molecular biomarkers, a nonlinear calibration curve is constructed to relate fixed biomarker concentrations to observed tracer levels. The biomarker concentration in an experimental sample can then be estimated by projecting the experimental tracer measurements through the inverse of the calibration curve. Once an estimate of the biomarker level has been calculated, it is often of interest to determine its variability. Typically, methods for estimating this variability assume that the biomarker variability is due solely to the uncertainty in the estimation of the calibration curve. A more complete analysis would combine this uncertainty with the variability in the processing and measurements of the sample, including, e.g., measurement error of laboratory procedures or variation in enzymatic activity in enzyme-linked immunosorbent assays or radioactivity counts in RIAs. In this paper, we present a method of estimating the variability of inverse estimates assuming there is variation arising from both the determination of the calibration curve and from the preparation and measurement of the experimental sample. Our method uses a resampling algorithm that avoids requiring many distributional assumptions present in alternative procedures, can be easily implemented, and is generalizable to any immunoassay procedure. Methods for incorporating our results in the estimation of variability for planning and analyzing biomarker experiments are discussed. We provide an example using RIA data for aflatoxin B1 detection. These biomarkers for aflatoxin exposure are used in the analysis of serum aflatoxin adduct levels in human and experimental samples, and they are important in hepatocellular carcinoma research.

Algorithms↗
PubMed1996

Environmental tobacco smoke exposure in inner-city children.

Exposure to environmental tobacco smoke (ETS) was assessed as part of a pilot study aimed at determining the extent of multiple toxicant exposures in children from inner-city areas of Baltimore, MD. Questionnaire data on sources of ETS and urinary cotinine were obtained in children considered at high risk for urban exposures because of previous or current overexposure to one inner-city environmental hazard, lead. Fifty-three (67.1%) of the 79 participants were exposed to ETS in the preceding 48 h as assessed by questionnaire. Cotinine was present in 77 (98.7%) of the 78 samples assayed with a mean of 79.2 ng/mg creatinine (54.7 ng/ml). Eighty % of children had cotinine values > or = 30 ng/mg creatinine, a level commonly associated with household ETS exposure. Levels in children without reported ETS exposure in their homes were also elevated (mean = 45.0 ng/mg creatinine). As expected, blood lead levels were elevated with a mean of 23.6 micrograms/dl. We conclude that these inner-city children have substantial exposures to both ETS and lead. Furthermore, the presence of elevated cotinine levels in children without known household exposure suggests that ETS should be considered an urban toxicant as well as an individual residential exposure.

Baltimore↗
PubMed1996

Use of carcinogen-DNA and carcinogen-protein adduct biomarkers for cohort selection and as modifiable end points in chemoprevention trials.

Clinical cancer prevention studies that use disease as an end point are of necessity large, lengthy and extremely costly. Development of the field of cancer chemoprevention is being accelerated by the application of intermediate markers to preclinical and clinical studies. One class of potentially useful biomarkers comes from studies of cancer risks derived from exposure to environmental carcinogens of both endogenous and exogenous origins. Sensitive and specific analytical methods have been developed for detecting and quantifying levels of covalent adducts of several important classes of carcinogens with cellular DNA and blood proteins at ambient levels of exposure. Such biomarkers can be applied to the preselection of exposed individuals for study cohorts, thereby reducing study-size requirements. Levels of these carcinogen-DNA and carcinogen-protein adducts can be modulated by some classes of chemopreventive agents. In this regard, these markers can also be used to rapidly assess the efficacy of preventive interventions such as exposure abatement and chemoprevention. However, the successful application of these biomarkers to prevention trials will be dependent upon prior determination of the associative or causal role of the marker to the carcinogenic process, establishment of the relationship between dose and response, and appreciation of the kinetics of adduct formation and removal.

Anticarcinogenic Agents↗
PubMed1996

Carcinogen-DNA and protein adducts: biomarkers for cohort selection and modifiable endpoints in chemoprevention trials.

Chemical-specific markers have been developed for a number of environmental carcinogens for use as molecular dosimeters of individual exposure. In addition to contributing substantially to the specificity and sensitivity of epidemiological studies aimed at determining the role of environmental agents in the etiology of human cancers, some of these biomarkers may prove to be useful endpoints for assessing the efficacy of preventive interventions including exposure avoidance or remediation and chemoprevention. Biomarkers of the biologically effective dose may be particularly useful in this context in that they provide a mechanistic linkage between exposure and disease outcome. The biologically effective dose reflects the amount of toxicant that has interacted with its critical molecular target and can be measured through a variety of analytical techniques as either carcinogen-DNA or -protein adducts. Approaches for the development and validation of aflatoxin adduct biomarkers are presented as a paradigm for the application of carcinogen-specific markers for cohort selection and as modifiable endpoints for assessing efficacy in chemoprevention trials.

Aflatoxin B1↗
PubMed1995

Molecular epidemiology and human risk monitoring.

Molecular epidemiologic research involves the identification of relations between previous exposure to some putative causative agent and subsequent biological effects in a cluster of individuals in populations. There is intensive current research in the field of molecular epidemiology, and this research has a direct impact on risk assessment processes. Many of the challenges facing risk assessors today can be addressed by research focused on developing a better understanding of (a) exposure characteristics or assessment, (b) the relationship between exposure and dose, and (c) the ultimate exposure/dose effect response relationship. Results from this research can be used to design and implement preventive interventions in at risk populations. Thus, the application of research in exposure assessment and molecular epidemiology to risk assessment and preventive interventions makes this a core program for public health.

Animals↗
PubMed1995

Biomarkers for assessing environmental exposure to carcinogens in the diet.

The major sources of human exposure to environmental carcinogens are through inhalation, ingestion, and percutaneous absorption. Food-borne carcinogens constitute the primary source of ingested carcinogens. Epidemiological analyses indicate that 20-50% of all human cancer is due to dietary causes, unfortunately, few specific etiologic agents have been identified. The use of chemical-specific molecular biomarkers in studies of several classes of carcinogens to which humans are exposed through the ingestion of food may provide the necessary data to identify these etiologic agents. These molecular biological markers can be classified into several categories: markers of exposure reflecting dose of toxic agents, markers of effect indicating a biological response to an exposure, and markers of susceptibility providing information about the inherent sensitivity of an individual to the toxic agent. By definition some of these markers are chemical-agent specific, such as a carcinogen-DNA or carcinogen-protein adduct, whereas others are biological process-specific such as the altered expression of a gene. In the future, information obtained from studies of molecular biomarkers in humans and experimental animals can be used for a range of public health applications from primary and secondary prevention to the design of clinical therapies. Aflatoxins have been extensively studied with validated biomarkers, and, currently, dietary polycyclic aromatic hydrocarbons (PAH) and heterocyclic amines (HA) derived from cooking meats and other staples are being intensively investigated. This article reviews some of the recent information on aflatoxins and describes future potential of PAH and HA biomarkers.

Aflatoxins↗
PubMed1995

Interindividual differences in the concentration of 1-hydroxypyrene-glucuronide in urine and polycyclic aromatic hydrocarbon-DNA adducts in peripheral white blood cells after charbroiled beef consumption.

Biological markers of internal dose and macromolecular dose from PAHs provide a potential means of assessing environmental exposure to PAHs through inhalation, ingestion and percutaneous absorption. In this study we examined the time course and interindividual variation of 1-hydroxypyrene-glucuronide (1-OHP-gluc) excretion in urine and PAH-DNA adduct formation in peripheral white blood cells (WBCs) after charbroiled (CB) beef consumption. As a marker of internal dose, 1-OHP-gluc was measured in human urine using immunoaffinity chromatography and synchronous fluorescence spectroscopy. PAH-DNA adducts were measured in WBCs by enzyme-linked immunosorbent assay (ELISA) in order to assess macromolecular dose. Ten healthy non-smoking males consumed identical amounts of CB beef on five consecutive days. Multiple blood and urine samples were collected before, during, and after the feeding period. The morning after the first day of CB beef consumption, individual urinary concentrations of 1-OHP-gluc increased 10- to 80-fold (range: 2.0-16.6 pmol/ml urine) above pre-feed baseline concentrations (0.23 +/- 0.11 pmol/ml) in the 10 subjects. 1-OHP-gluc concentration decreased to near baseline levels by 24-72 h after CB beef consumption ended. In contrast, PAH-DNA adducts in WBCs increased markedly in only four of 10 subjects during or after CB beef consumption. Significant interindividual variation was observed for both urinary 1-OHP-gluc concentration (P < 0.001 by Kruskal-Wallis) and PAH-DNA adduct levels (P < 0.005) during the feeding period. The mean urinary 1-OHP-gluc concentration for each subject during and immediately after (days 2-8) the feeding period was significantly correlated with their mean PAH-DNA adduct level in WBCs during the same time period (Spearman r = 0.79, P < 0.01). Evidence of segregation of the subjects into separate response groups based on level of urinary 1-OHP-gluc was observed, suggesting that discrete determinants may regulate the absorption, metabolism and/or excretion of ingested pyrene.

Adult↗
PubMed1995

Levels of aflatoxin-albumin biomarkers in rat plasma are modulated by both long-term and transient interventions with oltipraz.

The validation process for biomarkers to be used for monitoring the efficacy of preventive interventions in humans includes assessments of whether levels of the biomarker can be modulated in experimental models. From this perspective, the influence of two intervention protocols with the chemopreventive agent oltipraz on rates of formation and disappearance of aflatoxin-albumin adducts has been evaluated in rats chronically exposed to aflatoxin B1. Male F344 rats were treated daily with 20 micrograms aflatoxin B1, p.o. for 35 days. The first strategy employed a standard, long-term intervention in which basal AIN-76A diet was supplemented with 0.05% oltipraz beginning one week before AFB1 treatment and continuing throughout the period of carcinogen exposure. In this setting, treatment with oltipraz reduced the rate of formation of aflatoxin-albumin adducts such that steady-state levels were lowered by > 50% from control values of 400 pmol aflatoxin adducts/mg albumin. The time-course for reaching respective steady-state levels was unchanged, with or without oltipraz intervention. The second intervention strategy utilized a delayed, transient protocol in which oltipraz was fed for 2 weeks beginning 1 week after AFB1 dosing began and ending 2 weeks before AFB1 dosing was completed. This second strategy, which models clinical interventions in chronically exposed individuals, produced a steady decline in aflatoxin-albumin adduct levels that approached a 50% reduction by the end of the AFB1 exposure period. Development of smooth curve functions allowed for the estimation of the ratio of effects between the non-intervention and intervention groups as well as the simultaneous 90% confidence intervals for the aflatoxin-albumin adduct levels. These analyses indicated that long-term intervention with oltipraz produced a statistically significant reduction in levels of the aflatoxin-albumin biomarker at all times throughout aflatoxin exposure. By contrast, a statistically significant decrease in biomarker levels was not seen in the delayed, transient intervention protocol until the ninth day of the intervention. However, once achieved, significant differences from the control group were maintained for the remainder of the aflatoxin exposure period. These changes in aflatoxin biomarker levels are consistent with the cancer chemopreventive outcomes of these intervention protocols in rats. Collectively, these results support the utility of measuring this biomarker as a means for assessing the efficacy or chemopreventive interventions in individuals at high risk for aflatoxin exposure and development of hepatocellular carcinoma.

Aflatoxin B1↗
PubMed1995

Molecular biomarkers for aflatoxins and their application to human liver cancer.

The rationale for developing molecular biomarkers to monitor and assess risk from human exposure to aflatoxins have been justified by the association of these carcinogens with human liver cancer, a disease that causes at least 250000 deaths world-wide each year. The goal of our research has been the development of aflatoxin biomarkers based upon the knowledge of the biochemistry and toxicology of aflatoxins gleaned from both experimental and human studies. These biomarkers have been subsequently utilized in experimental chemoprotection models to provide data on the modulation of these markers under different situations of disease risk. Several of the aflatoxin specific biomarkers have been validated in epidemiologic studies and are now available to use as intermediate biomarkers in chemoprotection trials. This systematic approach provides encouragement for preventive interventions and should serve as a template for the development, validation and application of other chemical-specific biomarkers to cancer or other chronic diseases.

Aflatoxins↗
PubMed1995

Biomarkers and mechanistic approaches in environmental epidemiology.

Environmental epidemiological research involves the identification of relationships between previous exposures to putative causative agents and subsequent biological effects with study populations. Such relationships are often hard to fully characterize because of difficulties in accurately quantifying exposure, dose, and effect. Biomarkers are indicators, residing in biological systems or samples, of exposure, dose, effect, or susceptibility. Biomarkers of exposure indicate the presence of previous exposure to an environmental agent; a biomarker of dose bears a quantitative relationship to previous exposure or dose; these include exogenous substances, interactive products, or interactions that change the status of the target molecule. Biomarkers of effect indicate the presence and magnitude of a biological response to exposure to an environmental agent; these include endogenous components, or measures of the functional capacity or state of the system. Biomarkers of susceptibility indicate an elevated sensitivity to the effects of an environmental agent; these include the presence or absence of an endogenous component, or abnormal functional responses to an administered challenge. The development of molecular biomarkers for environmental agents is based upon specific knowledge of metabolism, interactive product formation, and general mechanisms of action. The validation of any biomarker-effect link requires parallel experimental animal and human epidemiological studies.

Biomarkers↗