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PubMed1993

Methods and concepts in detecting abnormal reproductive outcomes of paternal origin.

There is conclusive evidence that exposures of human males to ionizing radiation or certain chemicals can diminish sperm production and reduce fertility. Of approximately 100 chemical agents and mixtures that have been evaluated in men by semen analysis, about half (mostly drugs and a few occupational exposures) reduced sperm quantity and quality; several of these agents also affected the fertility of exposed men. It is now well recognized that the importance of the father in reproduction goes beyond fertilization. Abnormalities in paternal chromosomes (structural and numeric) have been found in various abnormal reproductive outcomes, including chromosomal abnormality syndromes among newborns. In rodent systems, exposure of males to mutagens before mating induces transmissible cytogenetic and genetic abnormalities as well as morphologic defects and cancer among offspring. Consistent with animal findings, there is growing epidemiologic evidence of associations between male exposures to exogenous agents and abnormal reproductive outcomes (fetal loss, birth defects, childhood cancer, etc.). However, no clear links have been established between exposure, mechanism of transmission, and abnormal reproductive outcomes. It is not known to what extent male-mediated birth defects and childhood cancer are due to genetic, epigenetic, or nongenetic causes. Viewed in a multigenerational context, the role of the father in abnormal reproductive outcomes is dependent on his exposure history and susceptibilities as well as those of his mate. Relevant exposures may occur any time between conception of the parents and production of their fertilizing gametes, including their development in utero, childhood, and adolescence. Efficient measurements (including biomarkers) of relevant exposure, early biologic effects, and susceptibility in human males are under development. An integrated approach is recommended for assessing male reproductive and genetic toxicity that utilizes biomarkers in (a) epidemiologic studies of exposed human populations, (b) risk characterization in sensitive laboratory species, and (c) in vivo and in vitro studies of the molecular mechanisms of action of toxicants. A special category of "bridging" biomarkers is needed for evaluating animal data for risk assessment and for discriminating among genetic, epigenetic, and nongenetic mechanisms of abnormal reproductive outcomes of paternal origin.

Adult↗
PubMed2006

Cerebrospinal fluid obstruction and malabsorption in human neonatal hydrocephaly.

INTRODUCTION: The pathophysiology involved in human neonatal high-pressure hydrocephalus (HC) includes both cerebrospinal fluid (CSF) malabsorption and obstruction. OBJECTIVE: The aim was to estimate the relative contribution between CSF malabsorption and obstruction in three different etiological groups of neonatal high-pressure HC by assessment of specific CSF biomarkers indicative of growth factor- and fibrosis-related CSF malabsorption (transforming growth factor beta-1 (TGF beta-1), aminoterminal propeptide of type 1 collagen (PC1NP)]. MATERIALS AND METHODS: Patients were subdivided into three groups. Group A: spina bifida HC (n=12); group B: non-haemorrhagic triventricular HC (n=4); and group C: posthaemorrhagic HC (n=6). To exclude for confounding differences in pro-inflammatory state between the three groups, interleukin-6 (IL-6) CSF concentrations were assessed. Consecutively, the CSF concentrations of TGF beta-1 and PC1NP were compared between the different groups. RESULTS: Median CSF concentrations of IL-6 were low and did not differ between groups. Median CSF concentrations of PC1NP were significantly lower in group A (median: 180 ng/ml, range 90-808) than in group C (median: 1,060, range 396-1194; p=0.002). TGF beta-1 concentrations were significantly higher in group C (median 355 pg/ml, range 129-843) than in groups A (median 103, range 78-675 pg/ml) and B (median 120 pg/ml, range 91-188; p=0.01 and 0.03, respectively). CONCLUSIONS: In neonatal posthaemorrhagic HC, high concentrations of malabsorption-related biomarkers contrast with lower concentrations in SB and non-haemorrhagic triventricular HC. During the early development of high pressure HC in SB neonates, CSF biomarkers strongly indicate that CSF obstruction contributes more to the development of HC than malabsorption.

Collagen Type I↗
PubMed1998

Fish cell lines as a tool in aquatic toxicology.

In aquatic toxicology, cytotoxicity tests using continuous fish cell lines have been suggested as a tool for (1) screening or toxicity ranking of anthropogenic chemicals, compound mixtures and environmental samples, (2) establishment of structure-activity relationships, and (3) replacement or supplementation of in vivo animal tests. Due to the small sample volumes necessary for cytotoxicity tests, they appear to be particularly suited for use in chemical fractionation studies. The present contribution reviews the existing literature on cytotoxicity studies with fish cells and considers the influence of cell line and cytotoxicity endpoint selection on the test results. Furthermore, in vitro/in vivo correlations between fish cell lines and intact fish are discussed. During recent years, fish cell lines have been increasingly used for purposes beyond their meanwhile established role for cytotoxicity measurements. They have been successfully introduced for detection of genotoxic effects, and cell lines are now applied for investigations on toxic mechanisms and on biomarkers such as cytochrome P4501A. The development of recombinant fish cell lines may further support their role as a bioanalytical tool in environmental diagnostics.

Animals↗
PubMed2003

SELDI ProteinChip(R) Array Technology: Protein-Based Predictive Medicine and Drug Discovery Applications.

Predictive medicine, utilizing the ProteinChip(R) Array technology, will develop through the implementation of novel biomarkers and multimarker patterns for detecting disease, determining patient prognosis, monitoring drug effects such as efficacy or toxicity, and for defining treatment options. These biomarkers may also serve as novel protein drug candidates or protein drug targets. In addition, the technology can be used for discovering small molecule drugs or for defining their mode of action utilizing protein-based assays. In this review, we describe the following applications of the ProteinChip Array technology: (1) discovery and identification of novel inhibitors of HIV-1 replication, (2) serum and tissue proteome analysis for the discovery and development of novel multimarker clinical assays for prostate, breast, ovarian, and other cancers, and (3) biomarker and drug discovery applications for neurological disorders.

Journal Article↗
PubMed2006

Identification of differentially expressed genes in Tetrahymena thermophila in response to dichlorodiphenyltrichloroethane (DDT) by suppression subtractive hybridization.

The insecticide dichlorodiphenyltrichloroethane (DDT) is persistent in the environment, and continues to cause health problems. Tetrahymena has potential as a model organism for assaying low levels of DDT and for analysing the mechanisms of its toxicity. We constructed the suppression subtractive hybridization library of T. thermophila exposed to DDT, and screened out 90 Expressed Sequence Tags whose expressions were significantly up- or downregulated with DDT treatment. From this, a series of important genes related to the DDT metabolism and detoxification were discovered, such as P450 gene, glutathione S-transferase gene and sterol carrier protein 2 gene. Furthermore, their expressions under different concentrations of DDT treatment were detected by real-time fluorescent quantitative PCR. The results show that Tetrahymena is a relevant and useful model organism for detecting DDT in the environment and for discovering biomarkers that can be used to develop specific bio-reporters at the molecular and genomic levels.

Animals↗
PubMedDate not supplied

Guidance values for the biomonitoring of occupational exposure. State of the art.

Biomonitoring was developed for the assessment of the health risks from exposure to chemicals at work, and the approaches and concepts of biomonitoring are derived from such exposures. At present, biomonitoring is increasingly used also to assess exposure from the environment. Biomonitoring and assessment of external exposure are complementing activities, where the exposure assessments are much more widely applied, especially when the number of chemicals concerned is considered; environmental analysis also offers the distinct advantage of speciation analysis--which is very poorly developed for biomonitoring. Biomonitoring on the other hand provides information on exposure from all sources, and via all absorption routes, and considers also accumulation of the chemical in the body. Bio monitoring using exposure biomarkers thus consider interindividual differences in the absorption, while use of effec biomarkers ideally also considers interindividual differences in sensitivity. Few effect biomarkers, however, have been validated. The major challenges of biomonitoring are the development of monitoring methods, which are inexpensive enough to be applied at a frequency that makes possible meaningful biomonitoring of chemicals with a short half-time; development of exposure biomarker guidance values specific to individual species of different metals; ex pansion of the repertoire of validated effect biomarkers; and validation and application to effect monitoring of the omic technologies. Another major challenge is a reconsideration of the basis of biomonitoring action limits to reflec the change in the work place: Biomonitoring should be adapted to assist in the generation of a healthy workplace which is capable of attracting workers, and assist them to perform their work effectively--rather than just to guarantee absence of serious health effects.

Air Pollutants, Occupational↗
PubMed2005

An immunohistochemical study of the development of sensorimotor components of the early fetal human spinal cord.

Sections from all spinal cord levels from 20 human fetuses, age range 7.5-17 gestational weeks (GW) were immunostained for non-phosphorylated neurofilaments (to reveal motoneurones, spinocerebellar neurones and other large neurones), the calcium-binding protein parvalbumin (large proprioreceptive afferents), growth-associated protein 43 kDa (growing axons), glial fibrillary acidic protein (radial glia), synaptophysin (synaptic terminals) the cell-cell recognition molecule ephrin A4 (EphA4) and the ETS transcription factor Er81 (subclasses of motoneurone and proprioreceptive neurone). Muscle afferents crossed the dorsal horn by 7.5 GW and innervated motoneurones by 9 GW. An alignment of glial fibres guided them from dorsal columns to ventral horn, at right angles to the radial glia. They continued to provide a dense innervation of motoneurone pools up to 17 GW. By 13 GW motoneurones were segregated into distinct columns, all of which expressed EphA4 although only certain lateral groups expressed Er81. However, Er81 expression was more widespread amongst dorsal root ganglion neurones. From 9 GW Clarke's column neurones were identified and by 14 GW were heavily innervated by parvalbumin-positive afferents whilst their efferent axons could be traced to the lateral funiculus. This investigation contributes towards a timetable for the functional development of human motor control and makes comparisons with well-studied rodent models.

Biomarkers↗
PubMedDate not supplied

Optimized blood cell profiling method for genomic biomarker discovery using high-density microarray.

High-quality biomarkers for disease progression, drug efficacy and toxicity liability are essential for improving the efficiency of drug discovery and development. The identification of drug-activity biomarkers is often limited by access to and the quantity of target tissue. Peripheral blood has increasingly become an attractive alternative to tissue samples from organs as source for biomarker discovery, especially during early clinical studies. However, given the heterogeneous blood cell population, possible artifacts from ex vivo activations, and technical difficulties associated with overall performance of the assay, it is challenging to profile peripheral blood cells directly for biomarker discovery. In the present study, Applied BioSystems' blood collection system was evaluated for its ability to isolate RNA suitable for use on the Affymetrix microarray platform. Blood was collected in a TEMPUS tube and RNA extracted using an ABI-6100 semi-automated workstation. Using human and rat whole blood samples, it was demonstrated that the RNA isolated using this approach was stable, of high quality and was suitable for Affymetrix microarray applications. The microarray data were statistically analysed and compared with other blood protocols. Minimal haemoglobin interference with RNA labelling efficiency and chip hybridization was found using the TEMPUS tube and extraction method. The RNA quality, stability and ease of handling requirement make the TEMPUS tube protocol an attractive approach for expression profiling of whole blood to support target and biomarker discovery.

Animals↗
PubMed2001

Considerations in the evaluation of surrogate endpoints in clinical trials. summary of a National Institutes of Health workshop.

We report on recommendations from a National Institutes of Health Workshop on methods for evaluating the use of surrogate endpoints in clinical trials, which was attended by experts in biostatistics and clinical trials from a broad array of disease areas. Recent advances in biosciences and technology have increased the ability to understand, measure, and model biological mechanisms; appropriate application of these advances in clinical research settings requires collaboration of quantitative and laboratory scientists. Biomarkers, new examples of which arise rapidly from new technologies, are used frequently in such areas as early detection of disease and identification of patients most likely to benefit from new therapies. There is also scientific interest in exploring whether, and under what conditions, biomarkers may substitute for clinical endpoints of phase III trials, although workshop participants agreed that these considerations apply primarily to situations where trials using clinical endpoints are not feasible. Evaluating candidate biomarkers in the exploratory phases of drug development and investigating surrogate endpoints in confirmatory trials require the establishment of a statistical and inferential framework. As a first step, participants reviewed methods for investigating the degree to which biomarkers can explain or predict the effect of treatments on clinical endpoints measured in clinical trials. They also suggested new approaches appropriate in settings where biomarkers reflect only indirectly the important processes on the causal path to clinical disease and where biomarker measurement errors are of concern. Participants emphasized the need for further research on development of such models, whether they are empirical in nature or attempt to describe mechanisms in mathematical terms. Of special interest were meta-analytic models for combining information from multiple studies involving interventions for the same condition. Recommendations also included considerations for design and conduct of trials and for assemblage of databases needed for such research. Finally, there was a strong recommendation for increased training of quantitative scientists in biologic research as well as in statistical methods and modeling to ensure that there will be an adequate workforce to meet future research needs.

Antiviral Agents↗
PubMedDate not supplied

The potential of the three-spined stickleback (Gasterosteus aculeatus L.) as a combined biomarker for oestrogens and androgens in European waters.

The majority of endocrine disruption studies in Europe have been on non-indigenous species (some of them tropical!)--and none of which has traits that make them suitable for the detection of androgenic compounds. To overcome these problems, we have been developing the stickleback as a model biomarker for testing the effect of endocrine disrupters in European waters. Its advantages are: it is the only fish with a quantifiable in vivo androgen and anti-androgen endpoint (the production of the glue protein, spiggin, by the kidney); it is the only fish in which it will be possible to simultaneously test oestrogenic and androgenic properties of compound; it has a genetic sex marker; it is found in all EU countries; it survives and breeds in both seawater and freshwater; it is extremely robust and can be readily deployed in situ; it displays a variety of pronounced reproductive behaviours; it has a simple and short life cycle, low fecundity and high egg/fry survival rates.

Androgens↗
PubMed1992

Leukemia inhibitory factor is expressed by the preimplantation uterus and selectively blocks primitive ectoderm formation in vitro.

Among its many activities, leukemia inhibitory factor (LIF) can maintain embryonic stem cell monolayers in a pluripotent undifferentiated state. Presuming that this might reflect its physiologic role during embryogenesis, we have examined LIF expression in the embryonic environment by RNase protection assays and have determined its in vitro effect on differentiating embryonic stem cell embryoid bodies. Of all adult tissues analyzed, LIF transcripts appear only in the uterus, where their level fluctuates with the estrous cycle, peaking after ovulation. LIF expression continues in the uteri of pregnant and pseudopregnant females, with a relative peak when blastocysts are normally present. As for its effects on in vitro differentiation, we have found that LIF blocks embryoid body differentiation only partially, yet in a precise manner. Using molecular markers to follow the differentiation of defined cell types, we demonstrate that LIF selectively inhibits the formation of primitive ectoderm, while permitting the differentiation of primitive endoderm. These results suggest a specific role for LIF in preimplantation mouse development.

Animals↗
PubMed2006

Analysis of protein expression (secretome) by human and mouse preimplantation embryos.

OBJECTIVE: To analyze the protein production into the surrounding medium (secretome) of both human and mouse embryos and correlate these findings with ongoing blastocyst development. Along with improvements in culture systems, there is renewed focus on the development of noninvasive viability assays in human IVF. Because the majority of biologic functions are carried out by proteins, it is important to study the dynamics of the proteome during embryonic development and its response to both internal and external stimuli. DESIGN: Experimental study. SETTING: Research laboratory. PATIENT(S): Couples undergoing infertility treatment donated with consent spent culture media for research. INTERVENTION(S): Analysis by time-of-flight mass spectrometry. MAIN OUTCOME MEASURE(S): Protein profiles of spent culture media. RESULT(S): Distinctive and significantly different secretome profiles were observed at each embryonic developmental stage (P<0.05). Correlation of day 5 secretome data with ongoing blastocyst development revealed an 8.5-kDa protein biomarker that was significantly up-regulated (P<0.05). The best candidate for this protein biomarker was ubiquitin, which has been implicated in the implantation process of mammalian species. CONCLUSION(S): This approach to analyze the secretome should not only further our understanding of embryo physiology but provide the basis for the development of noninvasive assays of embryo viability in human IVF.

Animals↗
PubMed2006

Pollution biomarkers in estuarine animals: critical review and new perspectives.

In this review, recent developments in monitoring toxicological responses in estuarine animals are analyzed, considering the biomarker responses to different classes of pollutants. The estuarine environment imposes stressful conditions to the organisms that inhabit it, and this situation can alter their sensitivity to many pollutants. The specificity of some biomarkers like metallothionein tissue concentration is discussed in virtue of its dependence on salinity, which is highly variable in estuaries. Examples of cholinesterase activity measurements are also provided and criteria to select sensitive enzymes to detect pesticides and toxins are discussed. Regarding non-specific biomarkers, toxic responses in terms of antioxidant defenses and/or oxidative damage are also considered in this review, focusing on invertebrate species. In addition, the presence of an antioxidant gradient along the body of the estuarine polychaete Laeonereis acuta (Nereididae) and its relationship to different strategies, which deal with the generation of oxidative stress, is reviewed. Also, unusual antioxidant defenses against environmental pro-oxidants are discussed, including the mucus secreted by L. acuta. Disruption of osmoregulation by pollutants is of paramount importance in several estuarine species. In some cases such as in the estuarine crab Chasmagnathus granulatus, there is a trade off between bioavailability of toxicants (e.g. metals) and their interaction with key enzymes such as Na(+)-K(+)-ATPase and carbonic anhydrase. Thus, the metal effect on osmoregulation is also discussed in the present review. Finally, field case studies with fish species like the croaker Micropogonias furnieri (Scianidae) are used to illustrate the application of DNA damage and immunosuppressive responses as potential biomarkers of complex mixture of pollutants.

Animals↗
PubMed2004

Splice variants as cancer biomarkers.

Inherited and acquired changes in pre-mRNA splicing have been documented to play a significant role in human disease development and many cancer-associated genes are regulated by alternative splicing. Loss of fidelity, variation of the splicing process, even controlled switching to specific splicing alternatives may occur during tumor progression and could play a major role in carcinogenesis. Splice variants that are found predominantly in tumors have clear diagnostic value and may provide potential drug targets. Moreover, understanding the process of aberrant splicing and the detailed characterization of the splice variants may prove crucial to our understanding of malignant transformation. This review discusses the basic mechanism of alternative splicing, alternative splicing in cancer-associated genes, tools to identify splice variants, and the development of clinical tests based on alternatively spliced biomarkers.

Alternative Splicing↗
PubMed2006

Crucian carp (Carassius carassius) VTG monoclonal antibody: development and application.

The vitellogenin (VTG) in fish has been used as an important biomarker for monitoring endocrine disrupting compounds (EDCs). This paper reports the development of a new monoclonal antibody (McAb) against the VTG of crucian carp (Carassius carassius). The McAb has a molecular weight of 149.4 kDa (heavy chain: 53.1 kDa; light chain: 21.6 kDa), and double diffusion indicated that it belongs to the IgG1 subclass. The titer is 10(5)-10(6) and the affinity constant (K(aff)) is 7.0 x 10(8)L/mol, showing the high specificity and sensitivity of the antibody. The established sandwich ELISA was sensitive with a detection limit of VTG 0.98 ng/mL. The cross-reactivity of antibody was detected in cyprinids such as rare minnow, zebrafish, and carp. This ELISA was used to detect the variation of VTG in crucian carp exposed to secondary effluent and reclaimed water from the Gaobeidian sewage treatment plant (SRP). The VTG induction in secondary effluent was higher than that in reclaimed effluent and the VTG levels in juvenile crucian carp increased with increasing exposure time. The VTG concentration in male fish from downstream of the Gaobeidian STP was 88.62+/-827.73 microg/mL, while that from a control site was undetectable.

Animals↗
PubMed2004

The comparative analysis of serum proteomes for the discovery of biomarkers for acute myeloid leukemia.

OBJECTIVE: Acute myeloid leukemia (AML) develops as the consequence of a series of genetic changes in a hematopoietic precursor cell. However, the definitive diagnostic protein biomarkers for AML are still unclear. In our study to identify the biomarkers for an initial diagnosis, detection of relapse, and monitoring the minimal residual disease in AML by a less invasive method, serum proteins reflecting alterations in their proteomes were analyzed. MATERIALS AND METHODS: We compared the two-dimensional electrophoresis patterns of human sera of 12 patients with AML with those of 12 normal subjects. The differentially expressed spots were identified by matrix-assisted laser desorption/ionization time-of-flight and electrospray ionization quadupole time-of-flight mass spectrometries. RESULTS: Eight proteins that expressed differentially in the AML group were found. The expression levels of alpha-2-HS-glycoprotein, complement-associated protein SP-40, 40, RBP4 gene product, lipoprotein C-III, and an unknown protein were downregulated in serum of AML patients, whereas the other three proteins, including immunoglobulin heavy-chain variant, proteosome 26S ATPase subunit 1, and haptoglobin-1 were upregulated. CONCLUSION: These results suggest that these proteins can be used as less invasive diagnostic and monitoring biomarkers of AML if further studies are done.

Adult↗
PubMed2005

Evaluation of matrix-assisted laser desorption/ionization-time of flight mass spectrometry proteomic profiling: identification of alpha 2-HS glycoprotein B-chain as a biomarker of diet.

Biomarkers have the potential to impact a wide range of public health concerns, including early detection of diseases, drug discovery, and improved accuracy of monitoring effects of interventions. Given new technological developments, broad-based screening approaches will likely advance biomarker discovery at an accelerated pace. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) allows for the elucidation of individual protein masses from a complex mixture with high throughput. We have developed a method for identifying serum biomarkers using MALDI-TOF and statistical analysis. However, before applying this approach to screening of complex diseases, we evaluated the approach in a controlled dietary intervention study. In this study, MALDI-TOF spectra were generated using samples from a randomized controlled trial. During separate feeding periods, 38 participants ate a basal diet devoid of fruits and vegetables and a basal diet supplemented with cruciferous (broccoli) family vegetables. Serum samples were obtained at the end of each 7-day feeding period and treated to remove large, abundant proteins. MALDI-TOF spectra were analyzed using peak picking algorithms and logistic regression models. Our bioinformatics methods identified two significant peaks at m/z values of 2740 and 1847 that could classify participants based on diet (basal vs. cruciferous) with 76% accuracy. The 2740 m/z peak was identified as the B-chain of alpha 2-HS glycoprotein, a serum protein previously found to vary with diet and be involved in insulin resistance and immune function.

Adult↗
PubMed1993

Osteoporosis: assessment of bone loss and remodeling.

Osteoporosis, the most common metabolic bone disorder, is a major health problem in older individuals, and especially in postmenopausal women throughout the world. It is characterized by low bone mass, structural deterioration, and an increased risk of fracture. The expected growth in the percentage of the world population over 65 years of age suggests that control of the chronic diseases of the elderly must be a major international priority. In order to design and implement appropriate prevention and treatment strategies for osteoporosis, it is necessary to assess the extent of the disease or condition in populations, and in individuals in a clinical setting. This review focuses on available and emerging techniques to measure bone mass or density, and on the role of biochemical markers of bone remodeling in the prediction of future bone loss. In order to prevent a disease that progresses without any obvious symptoms, it is important to determine not only the current status of bone mass and remodeling but also to develop methods to predict future bone loss. Different information is derived from each of the assessment approaches, and a combination of measures may be necessary to develop accurate predictive models.

Absorptiometry, Photon↗