Biomarkers of Susceptibility

These biomarkers are used to identify either individuals or populations who might have a different risk based upon differences that are inherent (i.e., genetic) or acquired (i.e., from life history and conditions). The inherent category includes the polymorphisms for genes encoding DMEs and for genes for the receptor and transcription factors regulating the expression of the genes for DMEs, as discussed in a previous section of this chapter. The category also includes polymorphisms for genes encoding components of developmental processes, although the latter are still not well understood. The acquired category includes previous disease conditions, antibody immunity, nutrition, other chemical and pharmaceutical exposures, and various capacities for homeostasis.

As a monitor, the placenta has been a key test organ for identifying such sensitive populations and their responses to environmental exposures. For example, Welch et al. (1969) and Nebert et al. (1969) demonstrated that AHH is induced in the human placenta of cigarette smokers. With the ever-improving tools for investigation, biomarkers now have moved from proteins and enzyme activities induced by polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene) and dioxin (Manchester et al. 1984; Gurtoo et al. 1983) to biomarkers of combined effect and exposure, such as mRNAs (e.g., CYP1A1) plus DNA adducts (Everson et al. 1987,1988; Perera et al. 1998).

The molecular probes to identify such subpopulations are useful as biomarkers not only for identifying individuals at risk but also for exploring the underlying mechanisms by which those individuals or populations are at risk by demonstrating allelic polymorphisms in a particular gene. As discussed above, gene-environment interactions have been noted for the induction of cleft palate in humans (Hwang et al. 1995) through a combination of cigarette smoking and TGF genotype. Alone, neither variable demonstrates an association with cleft palate. Such an example demonstrates the possibility for understanding why only a small percentage of a population exposed to a developmental toxicant might be at risk, but more important, it identifies a biological association that might lead to a mechanistic understanding of how a particular developmental defect might occur.

There are serious concerns about using the term “biomarkers of susceptibility” to describe a person’s particular set of alleles because these have a hereditary basis (e.g., slow acetylator activity, low G6PD activity, low 5,10-methylene tetrahydrofolate reductase activity, or high CYP1A1 activity). The committee emphasizes the need for a distinction between biomarkers of susceptibility reflecting inherent limitations versus those reflecting acquired limitations. The former require a full understanding of the complex genetic implications before they can be used. An allele encoding an altered DME, for example, might put the individual at increased risk for toxicity caused by one environmental chemical but at decreased risk for toxicity caused by another drug or environmental



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