Bone marrow, TCDD

TCDD causes bone marrow hypocellularity, with specific decreases in the total number of hematopoietic stem cells (HSC) and lymphocyte precursors.42 16 Exposure to TCDD also diminishes mRNA levels of recombination activating gene-1 and terminal deoxy-nucleotidyl transferase in bone marrow cells.47 The best characterized effect of TCDD on bone marrow is the impaired maturation of B cells. A single dose of TCDD causes a transient, time- and dose-dependent, and developmental stage-specific impairment in B cell maturation, with mature B cells affected first, followed by depletion of B cell progenitors.45-46... 

In summary, although numerous AhR-dependent changes in the bone marrow and thymus have been found in TCDD-treated mice, it appears that these effects are self-limiting in adult mice, as T and B cell numbers are not reduced in secondary lymphoid tissue except after exposure to high doses of TCDD or in the context of an adaptive immune response. More subtle effects, such as changes in the antigenic specificity of peripheral T and B lymphocyte populations, have not been documented. 

Luster, M., et. al., Examination of bone marrow, immunologic parameters and host susceptibility following pre- and postnatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), Int. J. Immunopharmacol., 2, 301, 1980. 

The AhR is expressed in bone marrow stromal cells [14] and human hematopoietic stem cells [15] and upon agonist binding the receptor translocates to the nucleus, resulting in altered transcriptional expression such as increased CYPlAl [16] and resulting in reactive oxygen species [17]. Nonpharmaceutical compounds such as TCDD, benzo(a)pyrene and benzene have been shown to induce hematotoxicity using this mechanism in vivo and in vitro [18, 19]. 

Mostly negative results were obtained in animal studies following oral exposure to 2,3,7,8-TCDD. Cytogenetic analysis of the bone marrow did not reveal any increase in chromosomal aberrations in... 

TCDD or estrogen results in thymic involution and modulation of particular bone marrow stem cell markers (Silverstone et al. 1994). However, the mechanism by which these compounds act are clearly different since potent antiestrogens block the effects of estrogen treatment without affecting... 

TCDD. Furthermore, lymph node atrophy (Allen et al. 1977) and bone marrow degeneration (Hong et al. 1989) were reported in monkeys after intermediate- and chronic-duration exposure to... 

Similarly, in vitro studies with lymphocytes, spleen cells, and bone marrow cells from 2,3,7,8-TCDD-pretreated mice indicated that 2,3,7,8-TCDD acts by an Ah locus-dependent mechanism to obstruct the formation of cytotoxic T cell generation from their precursors (Dooley et al. 1990 Holladay et al. 1991 Nagarkatti et al. 1984). A brief summary of the possible mechanisms of 2,3,7,8-TCDD immunotoxicity can be found in Section 2.4.2. 

Hexachlorobenzene acted like a weak Ah receptor agonist and caused an up to 40% decrease in specific hepatic cytosol binding of 2,3,7,8-TCDD in rat cells (Hahn et al. 1989b). Similarly, 2,3,7,8-TCDD-induced myelotoxicity and enzyme induction was antagonized by 1-amino-3,7,8-trichlorodibenzo-p-dioxin in B6C3Fj mice presumably by competitive binding to the cytosolic Ah receptor (Luster et al. 1986). Comparable effects were observed in vitro in murine bone-marrow-cells cultures. Treatment of Fischer 344 rats orally with di(2-ethylhexyl)phthalate (DEHP) before or after oral administration of... 

Utilize an in vivo bone marrow-thymus reconstitution model and mouse strains with arrested T-cell development to define the cellular and molecular targets of 2,3,7,8-TCDD that lead to thymic atrophy, and determine how these events relate to its overall action on the immune system. Dr. Gasiewicz is also determining what controls the functional activity of the Ah receptor, what target genes are affected in sensitive tissues, and how the modulated expression of these genes leads to the toxic responses observed after exposure to... 

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