• Modeling Mechanism：

  DMBA is activated by CYP1B1 metabolism (mainly local metabolism in bone marrow, with no significant effect from liver metabolism), rapidly inhibiting the proliferation and differentiation of bone marrow lymphoid (CFU-preB) and myeloid (CFU-GM) progenitor cells, leading to a reduction in bone marrow cells; at the same time, it causes a sustained decrease in peripheral blood lymphocytes and an initial decrease followed by an increase in neutrophils, ultimately resulting in immunosuppression, and this process depends on TNF receptor signaling and p53-related stress responses.

• Related Products：

  DMBA (T36696)

• Modeling Method：

  Experimental Subject：

  Mice, C57BL/6 and Cyp1b1⁻/⁻ transgenic strains, Female, 6 weeks old

  Dosage and Administration Route：

  10–50 mg/kg DMBA (dissolved in olive oil) Intraperitoneal (IP) injection or oral gavage

  Dosing Frequency and Duration Model：

  Single dose

• Validation：

  Hematopoietic function: CFU-preB and CFU-GM activities decreased by ≥50% within 6 hours, with the IP administration group showing sustained inhibition for up to 7 days, while myeloid progenitor cells recovered within 48 hours in the oral administration group; Bone marrow cells: The total cell count decreased by 60% within 48-72 hours after IP administration, with B220⁺ lymphocytes showing a sustained decrease (>90% within 7 days), and Gr-1⁺ myeloid cells showing an initial decrease followed by an increase; Peripheral blood: White blood cells, lymphocytes, and neutrophils all decreased by 50% within 6 hours, with lymphocytes showing sustained inhibition for up to 7 days, and neutrophils rebounding to 1.5 times the control group within 7 days; Specificity verification: Cyp1b1⁻/⁻ mice did not exhibit the above phenotypes, confirming that DMBA toxicity depends on CYP1B1 metabolism.

*Precautions： After the experiment, mice were euthanized with CO₂, and bone marrow cells were lysed with ACK buffer to remove red blood cells for use in CFU experiments or flow cytometry analysis.

*References：N'jai AU,et,al. Bone marrow lymphoid and myeloid progenitor cells are suppressed in 7,12-dimethylbenz(a)anthracene (DMBA) treated mice. Toxicology. 2010 Apr 30;271(1-2):27-35.

• Modeling Mechanism：

  DMBA, a polycyclic aromatic hydrocarbon carcinogen, activates PXR (mainly in Langerhans cells and other Langerin⁺ dendritic cells) and AHR (mainly in keratinocytes) after absorption through the skin. PXR and AHR regulate the expression of cytochrome P450 enzymes such as CYP3A and CYP1 family, respectively, promoting DMBA metabolic activation and inducing DNA damage (such as γH2AX aggregation). PXR deficiency can promote Langerhans cell migration and reduce the transfer of DMBA metabolites to keratinocytes, thereby alleviating DNA damage. However, humanized PXR mice show significantly enhanced DNA damage.

• Related Products：

  DMBA (T36696)

• Modeling Method：

  Experimental Subject：

  Mice, C57BL/6 background (including Pxr⁻/⁻, Ahr⁻/⁻, Langerin-DTR-EGFP, Tg-3A4/hPXR humanised strains), Adult

  Dosage and Administration Route：

  0.05% DMBA (0.5 mg/ml dissolved in acetone), Topically applied to mouse ear skin, Left ear treated with acetone as control

  Dosing Frequency and Duration Model：

  Single dose

• Validation：

  Molecular markers: Pxr, Cyp1a1, Cyp1b1, Cyp3a11 mRNA and PXR protein expression were upregulated in skin tissue, while Ahr mRNA showed no significant change; the number of γH2AX⁺ cells increased 5-fold after DMBA treatment in humanized PXR mice; Histology: γH2AX immunostaining showed DNA damage in basal keratinocytes, hair follicle cells, and Langerhans cells, with significantly reduced damage in Pxr⁻/⁻ and Ahr⁻/⁻ mice; Functional validation: Langerhans cells from Pxr⁻/⁻ mice migrated more towards draining lymph nodes, and Ccr7 mRNA expression was upregulated in the skin, while this phenotype was not observed in Ahr⁻/⁻ mice.

*Precautions： Mice were sacrificed 48 hours after modeling, and ear skin and drained lymph nodes were collected for gene expression detection, immunofluorescence staining, and flow cytometry analysis.

*References：Elentner A,et,al. Skin response to a carcinogen involves the xenobiotic receptor pregnane X receptor. Exp Dermatol. 2015 Nov;24(11):835-40.