Application of Toxicogenomic Analysis to Risk Assessment of Delayed Long-Term Effects of Multiple Chemicals, Including Endocrine Disruptors in Human Fetuses. (Commentary)

Article excerpt

Our previous studies analyzing umbilical cords show that human fetuses in Japan are exposed to multiple chemicals. Because of these findings, we believe it is necessary to establish a new strategy for examining the possible delayed long-term effects caused by prenatal exposure to multiple chemical combinations and evaluating the health risk to human fetuses. In this commentary we describe our attempts to apply toxicogenomic analysis of umbilical cords, using DNA microarray for future risk assessment. Because the umbilical cord is part of the fetal tissue, it is possible to estimate the effects of chemicals on the fetus by analyzing alteration of the gene expression. This type of toxicogenomic analysis could be a powerful and effective tool for developing a new risk assessment strategy to help investigators understand and possibly prevent long-term effects caused by fetal exposure to multiple chemicals. Worldwide cooperation is needed to establish a new stragegy for risk assessment using toxicogenomic analysis that focuses on the human fetus. Key words: delayed long-term effects, DNA microarray, human fetus, multiple chemicals, risk assessment, toxicogenomics, umbilical cord. Environ Health Perspect 111:803-809 (2003). doi:10.1289/txg.5958 available via[Online 12 November 2002]


Exposure to multiple chemical combinations occurs throughout our lives from air, water, soil, food, and household products. Environmental contamination by multiple chemicals, including endocrine disruptors (EDs), over the last 50 years has been suggested as a cause of human health disorders (Andersson et al. 2001; Colborn et al. 1996; Perera et al. 2002; Safe 2000; Sharpe and Skakkebaek 1993; Toppari et al. 1996). EDs are chemicals that disturb the function of natural hormones in humans and wildlife (Andersson et al. 2001; Colborn et al. 1996; Safe 2000). In animal experiments, potential EDs have adverse effects on the development and/or function of the reproductive and nervous systems, particularly when exposure occurs during fetal or neonatal periods (Colborn et al. 1996; Newbold 2001; Newbold et al. 1984; Williams et al. 2001). Similarly, human fetuses and infants are significantly more sensitive to a variety of environmental toxicants than adults (Charnley and Putzrath 2001; Needam and Sexton 2000; Perera et al. 2002). Several investigators have shown that fetuses and young children are especially vulnerable to the toxic effects of environmental tobacco smoke, pesticides, polychlorinated biphenyls (PCBs), and metals (Calabrese 1986; Jacobson and Jacobson 1996; Moore and Persaud 1998; Needleman 1979; Perera 1996; Whyatt and Perera 1995; WHO 1986).

The current risk assessment strategy, established in 1983 by the U.S. National Research Council (NRC), is based on the risk of exposure to only single chemicals and focuses on the adverse health effects on adults not children or fetuses (NRC 1983). It does not even suppose the risk of complex mixtures of chemicals to human fetuses. Several investigations have shown that combined effects of multiple chemicals enhance the proliferation of human breast cancer cells (Payne et al. 2001) and induce congenital anomalies in rats (Gray et al. 2001; Price et al. 2000). Our recent studies in Japan using human umbilical cords have shown that human fetuses are exposed to multiple chemicals (Mori 2001; Mori et al. 2001; Todaka and Mori 2002). There is genuine concern that these multiple chemical exposures in humans may cause delayed long-term adverse health effects. Therefore, in addition to the current risk assessment, a new method of health risk assessment of fetal exposure to multiple chemicals must be developed.

Toxicogenomics is now developing. It is defined as the study of the genes and their products, which are important in adaptive responses to toxic exposures (Iannaccone 2001). One applicable and efficient method for developing this assessment of fetal exposure to multiple chemicals is the toxicogenomic analysis of umbilical cords, using DNA microarray. …