Understanding the effect of immunotoxic compounds on hematopoietic and lymphopoietic cells during the critical windows of vulnerability and the persistence of that damage on postnatal immunity is complicated by at least two factors unique to immune responsive cells. The first is that cells at identical stages of lineage development may have differential susceptibility to toxic compounds based on their anatomic location and specific microenvironment. Lymphoid progenitor cells in the fetal liver may have different susceptibility to chemical exposure than cells with the same phenotype in the bone marrow. This is further complicated by the fact that resident cells in any of these tissues may have experienced toxic damage in other anatomic locations and then migrated to a different tissue site when they are assayed.
A second complication to understanding the effect of toxic compounds on hema-tolymphoid cells is that they have extensive renewal potential, and acute damage to hematopoietic cells may not be detectable later in life because of the unique ability of these cells to reconstitute losses (Bacigalupo et al. 2000). Numerous studies have demonstrated rapid recovery of immune responsive cells following cytotoxic drug therapy, and the ability of hematopoietic cells to recover following depletion is sufficiently robust to justify clinical utility of bone marrow transplantation (Banfi et al. 2001; Mudry et al. 2000). For that reason, relatively dramatic acute toxicity to either blood cell development or immune cell function may not lead to persistent detection of immunotoxicity. However, underlying damage to stem and progenitor cell populations, not detected by standard assays that enumerate numbers of cells responding to a single antigen, may in fact manifest itself when the hematopoietic system is stressed by myeloablative drug treatment (e.g., chemotherapy) or following bone marrow transplantation. For that reason, investigation of persistent damage to the blood-forming system of postnatal mice following prenatal exposure to toxic agents should address this issue.
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