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Identification of biomarkers for ovarian cancer using strong anion-exchange ProteinChips: potential use in diagnosis and prognosis.

One hundred eighty-four serum samples from patients with ovarian cancer (n = 109), patients with benign tumors (n = 19), and healthy donors (n = 56) were analyzed on strong anion-exchange surfaces using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry technology. Univariate and multivariate statistical analyses applied to protein-profiling data obtained from 140 training serum samples identified three biomarker protein panels. The first panel of five candidate protein biomarkers, termed the screening biomarker panel, effectively diagnosed benign and malignant ovarian neoplasia [95.7% sensitivity, 82.6% specificity, 89.2% accuracy, and receiver operating characteristic (ROC) area under the curve of 0.94]. The other two panels, consisting of five and four candidate protein biomarkers each, effectively distinguished between benign and malignant ovarian neoplasia and were therefore referred to as validation biomarker panel I (81.5% sensitivity, 94.9% specificity, 88.2% accuracy, and ROC = 0.94) and validation biomarker panel II (72.8% sensitivity, 94.9% specificity, 83.9% accuracy, and ROC = 0.90). The three ovarian cancer biomarker protein panels correctly diagnosed 41 of the 44 blinded test samples: 21 of 22 malignant ovarian neoplasias [10 of 11 early-stage ovarian cancer (I/II) and 11 of 11 advanced-stage ovarian cancer (III/IV)], 6 of 6 low malignant potential, 5 of the 6 benign tumors, and 9 of 10 normal patient samples. In conclusion, we have discovered three ovarian cancer biomarker protein panels that, when used together, effectively distinguished serum samples from healthy controls and patients with either benign or malignant ovarian neoplasia.

Biomarkers, Tumor↗

Intratumor heterogeneity of biomarker expression in breast carcinomas.

Small biopsy samples are used increasingly to assess the biomarker expression for prognostic information and for monitoring therapeutic responses prior to and during neoadjuvant therapy. The issue of intratumor heterogeneity of expression of biomarkers, however, has raised questions about the validity of the assessment of biomarker expression based on limited tissue samples. We examined immunohistochemically the expression of HER-2neu (p185erbB-2), epidermal growth factor receptor (EGFR), Bcl-2, p53, and proliferating cell nuclear antigen (PCNA) in 30 breast carcinomas using archived, paraffin embedded tissue and determined the extent of intratumor heterogeneity. Each section was divided into four randomly oriented discrete regions, each containing a portion of the infiltrating carcinoma. For each tumor, the entire lesion and four regions were analyzed for the expression of these markers. Scores of both membrane and cytoplasmic staining of HER-2neu and EGFR, scores of cytoplasmic staining of Bcl-2, and scores of nuclear staining of both p53 and PCNA were recorded. The intensity of staining and the proportion of immunostained cells were determined. A semiquantitative immunoscore was calculated by determining the sum of the products of the intensity and corresponding proportion of stained tumor cells. We analyzed both invasive (IDC) and in situ (DCIS) carcinomas. The Wilcoxon signed-rank test was used for paired comparisons between overall and regional immunoscores and between overall and regional percentages of stained cells. Spearman's correlation coefficients were used to assess the level of agreement of overall biomarker expression with each of the regions. Generalized linear models were used to assess overall and pair-wise differences in the absolute values of percent changes between overall and regional expression of biomarkers. For IDCs, there were no statistically significant differences in the expression of the biomarkers in terms of either the percentage of cells staining or the immunoscores when comparing the entire tumor with each region except for the lower EGFR expression of arbitrarily selected region 1 and lower p53 expression of region 1 compared to that of the entire tumor section. For DCIS, there were no statistically significant differences in the expression of the biomarkers between the entire tumor and each region except in PCNA of region 2 compared to that of entire tumor section. Positive correlation of immunoscores was observed between the entire tumor and each region as well as across all four regions for IDC. Similar observations were noted with DCIS except for HER-2neu and PCNA. No statistically significant differences were observed in the absolute values of percent changes of biomarker expression between overall and the four regions for both DCIS and IDC. Therefore, no significant intratumor heterogeneity in the expression of HER-2neu, Bcl-2, and PCNA was observed in IDC. Minor regional variations were observed for EGFR and p53 in IDC. Similarly, no significant regional variation in the expression of markers was observed in DCIS except for PCNA.

Biomarkers, Tumor↗

Role of biomarkers in monitoring exposures to chemicals: present position, future prospects.

Biomarkers are becoming increasingly important in toxicology and human health. Many research groups are carrying out studies to develop biomarkers of exposure to chemicals and apply these for human monitoring. There is considerable interest in the use and application of biomarkers to identify the nature and amounts of chemical exposures in occupational and environmental situations. Major research goals are to develop and validate biomarkers that reflect specific exposures and permit the prediction of the risk of disease in individuals and groups. One important objective is to prevent human cancer. This review presents a commentary and consensus views about the major developments on biomarkers for monitoring human exposure to chemicals. A particular emphasis is on monitoring exposures to carcinogens. Significant developments in the areas of new and existing biomarkers, analytical methodologies, validation studies and field trials together with auditing and quality assessment of data are discussed. New developments in the relatively young field of toxicogenomics possibly leading to the identification of individual susceptibility to both cancer and non-cancer endpoints are also considered. The construction and development of reliable databases that integrate information from genomic and proteomic research programmes should offer a promising future for the application of these technologies in the prediction of risks and prevention of diseases related to chemical exposures. Currently adducts of chemicals with macromolecules are important and useful biomarkers especially for certain individual chemicals where there are incidences of occupational exposure. For monitoring exposure to genotoxic compounds protein adducts, such as those formed with haemoglobin, are considered effective biomarkers for determining individual exposure doses of reactive chemicals. For other organic chemicals, the excreted urinary metabolites can also give a useful and complementary indication of exposure for acute exposures. These methods have revealed 'backgrounds' in people not knowingly exposed to chemicals and the sources and significance of these need to be determined, particularly in the context of their contribution to background health risks.

Biomarkers↗

Confirming the utility of four kidney biomarker tests in a longitudinal follow-up study.

In this follow-up study, 526 persons were followed for almost 5 years to assess the reversibility and predictive value of four kidney biomarkers in a field epidemiology setting. This study examined (a) whether elevations in urinary albumin, N-acetyl-beta-D-glucosaminidase, retinol-binding protein, and alanine aminopeptidase remained elevated at follow-up and (b) whether these initial elevations were predictive of kidney disease (as measured by markers of kidney dysfunction: serum creatinine, serum cystatin C, creatinine clearance, and urine osmolality) at follow-up. Study participants were 8-76 years of age at baseline and were followed for an average of 4.5 years. Approximately 50% of adults who had an elevated biomarker did not have an elevation at followup. Youths with elevated biomarkers at baseline, but who completed adolescence by the time of the follow-up, no longer had any elevations in biomarkers at follow-up. Adult participants who had elevated biomarkers and selected health conditions at baseline (diabetes and, to a lesser extent, heart disease, hypertension, gout, and urinary tract disease) were more likely to show early indicators of kidney impairment at follow-up. Participants with these health conditions and normal kidney biomarker values at baseline had kidney test results at follow-up that were similar to results of study participants who did not have these health conditions at baseline. The presence or absence of elevated biomarkers at baseline among generally healthy participants was not associated with the development of early indicators of kidney impairment at follow-up. This longitudinal study confirmed the utility of these four kidney biomarker tests as markers of preclinical organ dysfunction among adults with certain preexisting medical conditions.

Acetylglucosaminidase↗

Biomarkers of satiation and satiety.

This review's objective is to give a critical summary of studies that focused on physiologic measures relating to subjectively rated appetite, actual food intake, or both. Biomarkers of satiation and satiety may be used as a tool for assessing the satiating efficiency of foods and for understanding the regulation of food intake and energy balance. We made a distinction between biomarkers of satiation or meal termination and those of meal initiation related to satiety and between markers in the brain [central nervous system (CNS)] and those related to signals from the periphery to the CNS. Various studies showed that physicochemical measures related to stomach distension and blood concentrations of cholecystokinin and glucagon-like peptide 1 are peripheral biomarkers associated with meal termination. CNS biomarkers related to meal termination identified by functional magnetic resonance imaging and positron emission tomography are indicators of neural activity related to sensory-specific satiety. These measures cannot yet serve as a tool for assessing the satiating effect of foods, because they are not yet feasible. CNS biomarkers related to satiety are not yet specific enough to serve as biomarkers, although they can distinguish between extreme hunger and fullness. Three currently available biomarkers for satiety are decreases in blood glucose in the short term (<5 min), which have been shown to be involved in meal initiation; leptin changes during longer-term (>2-4 d) negative energy balance; and ghrelin concentrations, which have been implicated in both short-term and long-term energy balance. The next challenge in this research area is to identify food ingredients that have an effect on biomarkers of satiation, satiety, or both. These ingredients may help consumers to maintain their energy intake at a level consistent with a healthy body weight.

Animals↗

Recent developments in biomarkers for the early detection of lung cancer: perspectives based on publications 2003 to present.

PURPOSE OF REVIEW: Given the poor prognosis associated with lung cancer, the ability to diagnose lung cancer in its early stages is considered crucial to achieving decreased lung cancer mortality. Herein, we discuss recent advances in biomarker discovery and evaluation of their potential application in the clinical setting. RECENT FINDINGS: Novel potential biomarkers have been identified via new techniques including cDNA microarray analysis, comparative genomic hybridization, and proteomics. These factors have been evaluated in various validation studies including tissue microarrays, RT-PCR, and assays of bioactivity. The characterization of these potential biomarkers through analysis of pathways that have been associated with neo-plastic transformation may help to identify the precursor lesions that are associated with subsequent progression to invasive carcinoma. In addition, the past year has also produced intriguing results regarding the detection of biomarkers in easily accessible screening specimens such as sputa, serum, and exhaled breath. Recent advances in these aspects of biomarker identification for the early detection of lung cancer are reviewed. SUMMARY: Identification of new candidate biomarkers and improved applications of previously detected biomarkers show great promise for the ultimate establishment of practical lung cancer screening. While recent studies engender optimism for the creation of clinically applicable screening tests, the biomarkers that have been identified need larger, follow-up validational studies and further characterization as to their biologic importance.

Biomarkers, Tumor↗

Biomarkers for atherosclerosis: pathophysiological role and pharmacological modulation.

PURPOSE OF REVIEW: The aim of this article is to discuss the potential value of biomarkers for atherosclerosis in the assessment of risk for cardiovascular disease, in the pathogenesis of atherosclerosis, and in the monitoring of pharmacological treatment. RECENT FINDINGS: In an attempt to improve global cardiovascular risk prediction, considerable effort has been made in the discovery and characterization of soluble biomarkers which can go beyond the measure of total and LDL cholesterol levels. In particular, circulating molecules related to chronic inflammation have emerged as potential biomarkers for atherosclerosis. Evidence, obtained from in-vitro and in-vivo experimental models, has also documented that the majority of biomarkers play a pathological role in atherogenesis. Multiple screening of different biomarkers may therefore improve the assessment of risk, diagnosis, and prognosis for cardiovascular disease. In addition, soluble biomarkers have been shown to be modulated by hypolipidemic drugs and to be potentially useful in determining the clinical benefits of pharmacological therapies that do not alter serum lipid levels. SUMMARY: Altered levels of soluble biomarkers are associated with cardiovascular disease, and profiling of multiple biomarkers for atherosclerosis will be a useful indicator for better risk assessment, diagnosis, and prognosis, as well as monitoring pharmacological treatments for atherosclerosis.

Atherosclerosis↗

The role of biomarkers in clinical trials for Alzheimer disease.

Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer's Association's Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed.

Alzheimer Disease↗

Protein Biomarkers in Risk and Prognosis of Amyotrophic Lateral Sclerosis.

BACKGROUND: Plasma and cerebrospinal fluid (CSF) protein biomarkers in amyotrophic lateral sclerosis (ALS) may provide insight into disease mechanisms and yield clinically useful biomarkers. METHODS: Overall, 363 proteins in plasma and CSF from 198 patients with ALS and 125 matched controls were profiled using Olink assays. Associations with disease status, survival, and functional decline, as well as longitudinal biomarker stability across the disease course were assessed, together with network and enrichment analyses. ALS risk-associated biomarkers were externally validated in the UK Biobank (UKB). RESULTS: Overall, 125 proteins were significantly associated with at least one outcome (i.e., case status, risk, survival, or functional decline), and 21 were associated with three or more outcomes. NEFL was the most robust biomarker in plasma and CSF, alongside TNFRSF12A in plasma and CSF, EDA2R in plasma, and FABP4 in plasma and CSF. Most biomarkers remained stable longitudinally across the disease course. ALS risk-associated biomarkers were replicated in UKB, in which >&#x2009;3000 plasma proteins were measured in 52,990 participants, including 298 with ALS. Network and enrichment analyses highlighted their roles in immune response and extracellular-matrix remodeling, and their enrichments in the brain and T-cell subsets. Construction of an ALS risk-prediction model achieved an ROC-AUC of 0.72 in the UKB validation cohort. CONCLUSIONS: These findings suggest candidate protein biomarkers for ALS risk stratification, early detection, and clinical therapeutic monitoring.

Humans↗

Prognostic value of combined use of biomarkers of inflammation, endothelial dysfunction, and myocardiopathy in patients with ESRD.

BACKGROUND: Cardiovascular risk stratification is important in the clinical management of patients with end-stage renal diseases (ESRD) and biomarkers are increasingly used in these patients. METHODS: In a cohort of 246 dialysis patients without heart failure at baseline we tested the combined prognostic power of three well-established biomarkers: brain natriuretic peptide (BNP), C-reactive protein (CRP), and asymmetric dimethyl arginine (ADMA). The independent prognostic value of individual and combined biomarkers was estimated in separate Cox models, including standard risk factors in dialysis patients and comorbidities. RESULTS: When the prediction power of the three biomarkers was evaluated individually, BNP, ADMA, and CRP added significant predictive value (P< or = 0.01) to all-cause and cardiovascular mortality models and the explanatory gain attributable to these biomarkers were of similar degree (ranging from 3.3% to 5.7%). When the biomarkers were evaluated jointly, a score based on the BNP-CRP combination, increased by 9.9% (all-cause) and by 10.5% (cardiovascular) the explained mortality variance of standard Cox models and such gain in power was similar to that achieved by the CRP-ADMA combination (all-cause death 9.0% and cardiovascular death 8.4%). Of note, the explanatory gain derived by the simultaneous use of the three biomarkers was very similar (all-cause death 11.6% and cardiovascular death 10.5%) to that achieved by the use of two biomarkers. CONCLUSION: These findings indicate a potential role for CRP, BNP, and ADMA to be incorporated into diagnostic and therapeutic strategies aimed at detection and treatment of atherosclerotic complications and at preventing heart failure in the dialysis population.

Adult↗

Clinical and biomarker correlates of androgen-independent, locally aggressive prostate cancer with limited metastatic potential.

PURPOSE: We have identified a subset of patients exhibiting extended survival with metastases from androgenindependent prostate cancer of which the principal site of progression was the tumor primary. The purpose of this study was to evaluate the expression of selected biomarkers to characterize this subset of prostate cancer patients. EXPERIMENTAL DESIGN: A 105 core tissue microarray was constructed from primary tumor samples from 16 patients, with matched lymph node metastases in 5 cases. Immunohistochemistry was used to evaluate selected biomarkers associated with prostate cancer progression. Standard statistical methodologies were used to compute the distribution of time to progression and overall survival associations between pairs of biomarkers. Hierarchical clustering was done between groups of biomarkers, and we devised new methods to assess homogeneity of biomarker expression. RESULTS: The median interval from diagnosis to salvage surgery was 65 months. The profile of biomarker expression was notable for virtual absence of neuroendocrine features, high CD10, low matrix metalloproteinase (MMP)-9, high E-cadherin expression, and high membranous beta-catenin. The mean proliferative index was 12.1 +/- 10.1%, and the mean apoptotic index was 3.48 +/- 2.22%, and there was a significant correlation between these indices. Expression of the epidermal growth factor receptor was associated with phospho-AKT and proliferative index but inversely associated with phospho-STAT3. CONCLUSIONS: The cohort of prostate cancer patients, characterized by locally aggressive disease rather than lethal metastatic progression, was associated with a distinctive biomarker signature. The biomarker profile was, in general, more consistent with low-grade prostate cancer exhibiting local growth rather than metastatic progression. Ongoing studies will establish whether this unique subset of patients can be identified prospectively.

Aged↗

A simple method to combine multiple molecular biomarkers for dichotomous diagnostic classification.

BACKGROUND: In spite of the recognized diagnostic potential of biomarkers, the quest for squelching noise and wringing in information from a given set of biomarkers continues. Here, we suggest a statistical algorithm that--assuming each molecular biomarker to be a diagnostic test--enriches the diagnostic performance of an optimized set of independent biomarkers employing established statistical techniques. We validated the proposed algorithm using several simulation datasets in addition to four publicly available real datasets that compared i) subjects having cancer with those without; ii) subjects with two different cancers; iii) subjects with two different types of one cancer; and iv) subjects with same cancer resulting in differential time to metastasis. RESULTS: Our algorithm comprises of three steps: estimating the area under the receiver operating characteristic curve for each biomarker, identifying a subset of biomarkers using linear regression and combining the chosen biomarkers using linear discriminant function analysis. Combining these established statistical methods that are available in most statistical packages, we observed that the diagnostic accuracy of our approach was 100%, 99.94%, 96.67% and 93.92% for the real datasets used in the study. These estimates were comparable to or better than the ones previously reported using alternative methods. In a synthetic dataset, we also observed that all the biomarkers chosen by our algorithm were indeed truly differentially expressed. CONCLUSION: The proposed algorithm can be used for accurate diagnosis in the setting of dichotomous classification of disease states.

Algorithms↗

Comprehensive analysis of diagnostic biomarkers related to histone acetylation in acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) has become a serious disease that endangers human health, with high morbidity and mortality. Numerous studies have reported histone acetylation can result in the occurrence of cardiovascular diseases. This article aims to explore the potential biomarkers of histone acetylation regulatory genes (ARGs) in AMI patients. METHODS: Five AMI datasets were downloaded from the Gene Expression Omnibus (GEO) database. Next, ARG-related genes were gathered by gene set variation analysis (GSVA) and Spearman's correlation analysis. Subsequently, weighted gene co-expression network analysis (WGCNA) was performed to identify the module genes related to histone acetylation regulation. In the GSE60993 and GSE48060 datasets, the common differentially expressed genes (DEGs) between AMI and control samples were screened. Importantly, the intersecting genes were obtained by overlapping ARGs-related genes, common DEGs, and module genes. Then, the biomarkers in AMI were determined by machine learning, receiver operating characteristic (ROC) curves, and quantitative PCR (qPCR). In addition, immune analysis, drug prediction, molecular docking, and the lncRNA-miRNA-mRNA regulatory network targeting the biomarkers were analyzed, respectively. RESULTS: Here, a total of 18 intersecting genes were identified by overlapping 7,349 ARGs-related genes, 5,565 module genes, and 25 common DEGs. Further, five biomarkers (AQP9, HLA-DQA1, MCEMP1, NKG7, and S100A12) were obtained, and a nomogram was constructed and verified based on these biomarkers. Notably, the biomarkers were significantly associated with CD8 T cells and neutrophils. In addition, the drugs related to biomarkers were predicted, and ATOGEPANT with the molecular target (S100A12) had a high binding affinity (docking score = -10&#xa0;kcal/mol). CONCLUSION: AQP9, HLA-DQA1, MCEMP1, NKG7, and S100A12 were identified as biomarkers related to ARGs in AMI, which provides a new perspective to study the relationship between ARGs and AMI.

Humans↗

Air toxics: biomarkers in environmental applications--overview and summary of recommendations.

On April 27-28, 1995, the National Urban Air Toxics Research Center hosted a Symposium on Air Toxics: Biomarkers in Environmental Applications. The purpose of the symposium was to define the current state of the art in the application of biomarkers for environmental exposures to benzene, toluene, styrene, 1,3-butadiene, polycyclic aromatic hydrocarbons, manganese, and chromium. Sensitive, specific, and cost-effective biomarkers of exposure, effect, and susceptibility may greatly improve our knowledge of the human health impacts of air toxics exposures. Presentations were made on the first day that provided state-of-the-art background for the need, use, and ethical considerations in biomarker research and applications. In workshops held during the symposium, a number of recommendations were made regarding the use and need for additional research with biomarkers. In general, the sensitivity and specificity of biomarkers for environmental exposures, need to be improved. Reliable effect and susceptibility biomarkers are not available for these compounds. More research needs to be done to establish and evaluate biomarkers, linked to health effects through mechanistic studies, at environmentally relevant exposure levels.

Air Pollutants↗

Biomarkers in pediatric environmental health: a cross-cutting issue.

It is not yet known the extent to which the environment adversely affects the health of the developing individual. Difficulties in this determination are the problems of a) the assessment of exposure, b) the long latency of many diseases induced by the environment, c) the number of confounding exposures, and d) the extrapolation of animal models to critical stages of human development. Biomarkers have the potential to be quantitative dosimeters of exposure and biologic effective dose, as well as early warning signals of biologic effect. Biomarkers may document interindividual susceptibilities, as well as defining critical windows of exposure. To be useful, biomarkers need to be validated in terms of their specificity and sensitivity. Biomarkers are useful across all disciplines including asthma and respiratory problems, developmental neurotoxicity, childhood cancer, and endocrine disruptors. Biomarkers have not been developed nor used widely in pediatric environmental health. Research by our group and others has documented the validity of biomarkers in pediatric environmental health. Advances in the field of biomarkers may have important implications for the detection, prevention, and treatment of environmentally induced diseases in children. Ongoing validation of promising biomarkers should be a research priority.

Age Factors↗

Synergistic approaches to clinical oncology biomarker discovery.

Biomarkers in the clinical oncology field can have tremendous therapeutic impact especially if the marker is detected before clinical symptoms. This impact can be extended to the evaluation of clinical oncology treatments allowing evaluation of potential compounds to determine their efficacy in the disease treatment. The discovery of clinical biomarkers can consume time, resources and costs. Therefore, it is important that the most effective strategies are employed to discover these biomarkers. These strategies may include the integration of available genomic, proteomic and histopathological technologies, which could reduce the costs and aid in the validation of the biomarker. Certainly the type of biomarker needed to address a particularly defined problem will drive the type of technology. However, a single biomarker to diagnose a specific cancer can be as elusive as relying on a single technology. This review examines some of the technologies used to discover biomarkers and presents the use of combinatorial technical synergies to discover and validate potential clinical oncology biomarkers.

Biomarkers, Tumor↗

Aflatoxin and hepatitis B virus biomarkers: a paradigm for complex environmental exposures and cancer risk.

The use of biomarkers in molecular epidemiology studies for identifying stages in the progression of development of the health effects of environmental agents has the potential for providing important information for critical regulatory, clinical and public health problems. Investigations of aflatoxins probably represents one of the most extensive data sets in the field and this work may serve as a template for future studies of other environmental agents. The aflatoxins are naturally occurring mycotoxins found on foods such as corn, peanuts, various other nuts and cottonseed and they have been demonstrated to be carcinogenic in many experimental models. As a result of nearly thirty years of study, experimental data and epidemiological studies in human populations, aflatoxin B(1) was classified as carcinogenic to humans by the International Agency for Research on Cancer. The long-term goal of the research described herein is the application of biomarkers to the development of preventative interventions for use in human populations at high-risk for cancer. Several of the aflatoxin specific biomarkers have been validated in epidemiological studies and are now being used as intermediate biomarkers in prevention studies. 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 subsequently been utilised in experimental models to provide data on the modulation of these markers under different situations of disease risk. 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. 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↗

Biomarkers of reproductive toxicity.

A biomarker can be broadly defined as any biological index capable of being measured, which is associated with or indicative of a defined biological endpoint such as a developmental or disease stage. Identification and verification of anatomical, endocrine, cellular and molecular biomarkers is crucial for successful clinical diagnosis and treatment of toxicity and disease, as well as basic toxicological, epidemiological and other research. Various biomarkers of reproductive development and health have been identified, including those associated with pubertal development, adult reproductive health and pregnancy outcome. Herein we discuss those in situ biomarkers which have been more closely associated with toxicant action on the reproductive system. Biomarkers of toxicant exposure and susceptibility are addressed, but the majority of the review focuses on those biomarkers which may prove useful for determining current pathophysiological status or predicting future adverse outcomes. In males these are primarily associated with altered spermatogenesis and sperm parameters, and in females with altered endocrine function. We conclude that although few robust in situ biomarkers are currently available which are specific for toxicant exposure, susceptibility or effect in reproductive systems, there is expectation that post-genomic technologies offer a new paradigm for identifying and verifying such biomarkers as may exist.

Animals↗