One more kind of molecular-stress and checkpoint pathway should be noted: the apoptosis pathway, which is also a signaling pathway (see Table 6-2). It can be activated by either extracellular or intracellular signals and leads to the “programmed” death and destruction of a cell. It is a tightly controlled process in which a cell is destroyed but neighboring cells are unaffected. Apoptosis is not found in single-celled organisms. It is an invention of metazoa and is used in normal embryonic development as well as in recovery attempts of teratogen-damaged embryos. In normal development, where apoptosis is also known as programmed cell death, it is important in the shaping of tissues and organs (e.g., the elimination of cells from the interdigital spaces of the human hand). Cells undergoing apoptosis are found throughout most embryonic mesenchymal tissues, presumably reflecting the elimination of cells that have not been able to successfully integrate the signals impinging upon them. Some mouse mutants, such as Hammertoe, fail to initiate the normal amount of programmed cell death in normal limb development, and an abnormal limb results (Zakeri et al. 1994).

Apoptosis is also the ultimate molecular-stress and checkpoint pathway, for it eliminates cells too damaged to be restored to a normal state by the various repair and checkpoint pathways. For example, if DNA repair is incomplete and the cell attempts to divide, it is killed and autolyzed. It has been proposed that cell death is less detrimental to the multicellular organism than having live cells with highly modified DNA, perhaps proliferating uncontrollably and interacting aberrantly with other cells. Apoptotic cell death is an early response of embryos to many if not all teratogens (Scott 1977; Knudsen 1997). Often, teratogen-induced cell death occurs in the areas of normal programmed cell death but in an expanded area (Alles and Sulik 1989). If cell death is not too extensive, embryos are thought to recover by compensatory cell proliferation (Sugrue and DeSesso 1982). Excessive teratogen-induced cell death, however, is directly linked to abnormal development. For example, eye defects induced by 2-chloro-2'-deoxyadenosine are associated with excessive teratogen-induced cell death (Wubah et al. 1996).

The intracellular signals of apoptosis are not yet known. Key components in the execution phase of the apoptotic pathway are the intracellular cysteinyl-aspartate proteases known as caspases, particularly caspase-3 (Colussi and Kumar 1999). These enzymes are normally present in all cells as inactive precursors that become activated by cleavage at specific internal motifs, in response to cytochrome c leaked by mitochondria into the cell’s cytoplasm. Once activated, these caspases function to degrade specific target substrates such as poly(ADP-ribose)-polymerase (PARP), DNA-PKs, and lamins. Thereafter, chromosomal DNA is broken down. Treatment of cells with such developmental toxicants as hyperthermia, cyclophosphamide (an alkylating agent), and sodium arsenite (thiol oxidant) leads to the activation of caspase-3, cleavage of PARP, fragmentation of DNA, and cell death (Mirkes and Little 1998). It is not known how cells in the embryo recognize exposure to a developmental toxicant and initiate the apoptotic



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