Our initial results demonstrated that 2,3,7,8,-TCDD, the prototype of the class, could suppress antibody production following either subchronic exposure (14 day) or direct exposure with cultured splenocytes from untreated mice. Direct exposure produced an equivalent dose-related suppression of a variety of in vitro antibody responses requiring a differential role by accessory cells, thereby suggesting that the B-lymphocyte was the primary target. The IC50 of this suppression was about 10 nM, which suggested that it may be receptor mediated. Our results have indicated that direct exposure to either 2,3,7,8-TCDD (1-30 nM) or 3-methylcholanthrene (2-400 uM), a PAH with a strong affinity for the Ah receptor (i.e., the receptor implicated in other actions by the dioxins), produced a dose-related and equivalent suppression of the in vitro antibody response by spleen cells from both the B6C3F1 mouse (Ah+) and the DBA/2 mouse (Ah-). Previous results have indicated that 2,7-dichlorodibenzo-p-dioxin (DCDD) can neither bind to the Ah receptor nor produce the associated effects, including induction of cytochrome P1-450. Our results have indicated that direct exposure to 2,7-DCDD can suppress the in vitro antibody response and that the concentrations required to produce this suppression were similar in magnitude to 2,3,7,8-TCDD (i.e., 1-30 nM). An initial experiment with subchronic exposure (14 days) to 2,7-DCDD demonstrated a suppression of the antibody response (about 50% with 0.1 ug/kg/day) without any induction of arylhydrocarbon hydroxylase (i.e., highest dose tested was 10 ug/kg/day). In the same experiment, subchronic exposure to 2,3,7,8-TCDD at 1 ug/kg/day produced both effects. These results are significant since they indicate that the dioxin-induced suppression of the antibody response need not be associated with the Ah receptor. Thus, the preliminary results of this investigation may be the first indications for another class of dioxin receptors. From a toxicological viewpoint, these results indicate that the existing structure-activity relationship may not account for all toxicity associated with this class of chemicals, and certainly cannot account for the immunotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES002520-04A1
Application #
3249846
Study Section
Toxicology Study Section (TOX)
Project Start
1981-09-01
Project End
1989-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Overall Medical
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Henriquez, Joseph; Zhou, Jiajun; Li, Jinpeng et al. (2017) Application of gene specific mRNA level determinations in individual cells using flow cytometry-based PrimeFlow™ in immunotoxicology. Toxicol Appl Pharmacol 337:39-44
Li, Jinpeng; Bhattacharya, Sudin; Zhou, Jiajun et al. (2017) Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis. J Immunol 199:3504-3515
Kovalova, Natalia; Nault, Rance; Crawford, Robert et al. (2017) Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells. Toxicol Appl Pharmacol 316:95-106
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Phadnis-Moghe, Ashwini S; Li, Jinpeng; Crawford, Robert B et al. (2016) SHP-1 is directly activated by the aryl hydrocarbon receptor and regulates BCL-6 in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Appl Pharmacol 310:41-50
Kovalova, Natalia; Manzan, Maria; Crawford, Robert et al. (2016) Role of aryl hydrocarbon receptor polymorphisms on TCDD-mediated CYP1B1 induction and IgM suppression by human B cells. Toxicol Appl Pharmacol 309:15-23
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De Abrew, K Nadira; Phadnis, Ashwini S; Crawford, Robert B et al. (2011) Regulation of Bach2 by the aryl hydrocarbon receptor as a mechanism for suppression of B-cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 252:150-8
Sulentic, Courtney E W; Kaminski, Norbert E (2011) The long winding road toward understanding the molecular mechanisms for B-cell suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 120 Suppl 1:S171-91
Lu, Haitian; Crawford, Robert B; Kaplan, Barbara L F et al. (2011) 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated disruption of the CD40 ligand-induced activation of primary human B cells. Toxicol Appl Pharmacol 255:251-60

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