William W. Au

Biomarkers of exposure and biological effects have frequently been used to monitor populations for their exposure to toxic substances and for the prediction of disease risk, such as cancer. Current interest is focused on improving the use of biomarkers to better understand biological mechanisms for improved risk assessment. Such improvements involve the understanding of inter-individual variations in response to exposure, integration of genomic and proteomic technologies into biomarker studies, development of functional biomarkers, and the use of high tech procedures like biosensors and lab-on-a-chip approaches. The latter two approaches can provide unique contributions by providing specific and real-time reporting of excessive exposure. Based on the generation of more reliable information regarding exposure-specific effects, biological mechanisms, and health risk, more realistic prevention and intervention protocols have been implemented. The usefulness and application of these biomarkers and technologies will be presented.

We have reported that a gene therapy approach, using a dominant-negative estrogen receptor blocker (DN) gene, can cause cell death in cervical cancer cells in vitro. We investigated the mechanisms for enhanced cell killing when DN was combined with cisplatin (CP) and paclitaxel (TX). Cells were transduced with DN at 24 h and/or treated with drugs at 48 h, and harvested at 48 and 72 h after transduction. Effects were determined using the MTT cytotoxic, and TUNEL and caspase-3 activity apoptotic assays. Each agent induced cytotoxic and apoptotic effects, and activated caspase-3. In the combined treatments, significant synergistic effects were observed based on the MTT and TUNEL assays, but with antagonistic caspase-3 activation effect. The enhanced cell killing effect was mediated by the initiation of new and multiple mechanisms, particularly via caspase-independent pathways.

High frequencies of inherited DNA sequence variations (polymorphisms) are found in the human population. The involvement of polymorphic genes (especi

A variety of biomarkers have been used to study worker populations, and these studies have achieved different levels of success in the improvement of occupational health. Successful application of biomarker research is dependent upon several important factors: ability to identify hazardous substances from the exposure to a variety of substances, relevance to the development of disease, and usefulness for health risk assessment. Besides the traditional biomarkers for exposure, biological effects, and health risk, new biomarkers for susceptibility and genome-wide responses are being used to improve our understanding of occupational health at a higher and, perhaps, more precise level. In addition, there is a continued need to develop and apply biomarkers that can be used to provide real-time detection of excessive exposure to hazardous substances in the workplace, especially from unexpected fugitive emissions. These topics are discussed in the review.

Genetic variations have generally been accepted to be the major mechanism for the differences observed in susceptibility to cancer. However, extensive investigations on genotype‐disease associations have not produced consistent results. The inconsistency may be caused by many factors, such as improper study design, insufficient sample size, complexity of the traits under investigation, heterogeneity of the study subjects, incorrect assumptions about the underlying genetic architecture, misclassification of the disease, improper selection of potential alleles, and overinterpretation of the data. Besides these “traditional” factors, a recent problem is that the function of many variant genotypes is unknown, especially with regard to polymorphic DNA repair genes. Therefore, in addition to the genotype‐disease relationship, it may be prudent to step back and investigate the fundamental role of genetic variation in the development of cancer. The latter studies may focus on understanding the genotype‐exposure interactions and evaluating genotype‐health risk associations. This review will emphasize the use of relevant biomarkers and polymorphic DNA repair genes for investigations. These data will be useful for a better understanding of the complexity of disease causation and development, developing new models for human disease, and identifying pathways for prevention of cancer. Environ. Mol. Mutagen., 2005.