Expert Views :: The Hox Code, A Target for Embryonic Toxicity
William A. Toscano

In about 400 BCE, Hippocrates recognized that the environment had effects on human health and development. This concept persisted until the mid 1800’s. Over the course of many years of scientific development and sophistication, this concept was forgotten by biologists as the emphasis turned to genetic parameters that define development. For many years, it was felt that all problems, large and small in humans and wild life could be explained by one’s genetic make up.

In the early 1960s, Rachael Carson revived the concept that the environment played an important role in the health of animals in her classic book “Silent Spring” (Carson, 1962). There was much controversy surrounding her observations and she received vitriol from many interest groups. In the 1970’s and 1980’s, various conferences raised the prospect that the environment may be playing a role in development, but there was not much research activity, save for a small group of dedicated scientists (nicely recounted in a recent popular book (Krimsky, 2000)). Now, biologists are beginning to recognize the importance of environment-gene interactions on organism health, and particularly on development. Several interesting reviews of the effects of environment on development have appeared (Gilbert, 2001; van der Weele, 1999). Those reviews focus on such environmental effects on development as oxygen tension, temperature, and pH. Some attention is paid to other factors such as “environmental hormones” but there has not been a groundswell of enthusiasm from mainstream biologists to “solve” the question of what environmental agents are doing to developing organisms. Why is this so? I think that one possibility is that we have not found interesting new insights that would attract attention of mainstream biologists. For example, observing that a chemical may affect a receptor thereby affecting gene expression does not really add great insight into mechanisms by which agents bring about malevolent actions.

In a recent paper, David Crews defined the “old” toxicology as, “a subject based on carcinogenesis and mortality”, and suggested that the “new” toxicology uses a developmental model, delayed expression of toxicity, and lack of threshold (Crews et al., 2000). I agree with most of the Crews model, but when I think of toxic action, I believe we should be thinking in terms of disruption of information transfer within an organism. We know that cells are bombarded with many signals that must be sorted out, transduced and translated into information that will yield a specific cellular response. The question becomes one of what happens when embryonic cells receive signals that deceive cells. This has been addressed in a several reviews by John McLachlan (McLachlan, 1993; McLachlan, 2001). That environmental chemicals are acting at specific cellular receptors is an attractive proposal that has much credibility. However, signaling does not stop there. I think that we must now focus efforts on understanding the consequences on downstream signals that are affected, which will cause developmental disruption.

I would like to suggest that an important, but overlooked target of environmental agents, is a group of genes called Hox genes. Hox genes encode for proteins that are transcription factors, known as the homeodomain-containing proteins, or homeoproteins, which are important in regulating many aspects of embryonic development (for a recent review, see (Gehring, 1998; Lufkin, 2001). Hox genes control morphogenesis of the embryo and they encode positional information. Together the group of homeodomain proteins constitutes a code that controls morphogenesis. As I was looking at the Hox code, I was reminded of a management system that I read about many years ago. This was the PERT-CPM (Program Evaluation and Review Technique - Critical Path Management) system of management that was developed by Admiral Hymen Rickover and his staff as they were developing the Polaris nuclear submarine project in the 1950s. This program tracked the progress, accuracy and schedule of the plan (Laurant, 1998). A built-in feature of this management plan is to monitor effects of proposed changes that developed during the course of the project. Hox genes form a biological PERT-CPM system of management for developing organisms. The Hox code is Mother Nature’s PERT-CPM system that allows the organism to recognize which processes, if delayed or altered will disrupt the entire process.

Understanding the action of environmental toxicants on genetic signals that determine anterior-posterior axis formation and morphogenic development remain the greatest challenge for developmental toxicologists. Although the mechanisms underlying these events are still not well understood, the discovery of homeobox-containing genes provided a wealth of information about the complicated cell-cell communication that occurs during early development. The coordination of many genetic signals is required for normal development of individual structures. This coordination is further regulated by a number of environmental and hormonal cues. Hox proteins are genetically conserved; control the embryonic development of the animal body plan and critically important in many areas of development, such as patterning of the embryo and cell-type. Concentration of Hox genes is as important as the combination of Hox proteins expressed in a particular cell.

Mechanisms of toxicant-hox interactions will be important to fully understand the action of hormonally active agents in development.

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