Diindolylmethane inhibits cervical dysplasia, alters estrogen metabolism, and enhances immune response in the K14-HPV16 transgenic mouse model.
This study was designed to establish whether 3,3'-diindolylmethane (DIM) can inhibit cervical lesions, alter estrogen metabolism in favor of C-2 hydroxylation, and enhance immune function in the K14-HPV16 transgenic mouse model. Mice were bred, genotyped, implanted with E(2) pellets (0.25 mg/90-day release) under anesthesia, and divided into groups. Wild-type and transgenic mice were given either AIN76A diet alone or with 2,000 ppm DIM for 12 weeks. Blood and reproductive tracts were obtained. Blood was analyzed for estrogen metabolites and IFN-gamma. The cervical transformation zone was sectioned and stained for histology. Estradiol C-2 hydroxylation and serum IFN-gamma levels were significantly increased over controls in wild-type and transgenic mice receiving DIM. In wild-type mice without DIM, hyperplasia of the squamous epithelium was observed. Wild-type mice fed DIM displayed a normal thin epithelium. In transgenic mice without DIM, epithelial cell projections into the stroma (papillae) were present. An additional degree of nuclear anaplasia in the stratum espinosum was observed. Dysplastic cells were present. Transgenic mice fed DIM displayed some mild hyperplasia of the squamous epithelium. DIM increases estrogen C-2 hydroxylation in this model. Serum INF-gamma was increased, indicating increased immune response in the DIM-fed animals. Histopathology showed a marked decrease in cervical dsyplasia in both wild-type and transgenic mice, indicating that DIM delays or inhibits the progression from cervical dysplasia to cervical cancer. Using the K14-HPV16 transgenic mouse model, we have shown that DIM inhibits the development of E6/E7 oncogene-induced cervical lesions.
Sepkovic
Daniel W
DW
The David and Alice Jurist Institute for Research, Hackensack University Medical Center, Hackensack, New Jersey 07601, USA. dsepkovic@humed.com
Stein
Johann
J
Carlisle
Antoine D
AD
Ksieski
H Barbara
HB
Auborn
Karen
K
Bradlow
H Leon
HL
D000818:Animals; D016588:Anticarcinogenic Agents / Q000097:blood / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D007109:Immunity / Q000187:drug effects; D007211:Indoles / Q000097:blood / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000502:physiology; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*
D016588:Anticarcinogenic Agents; D004967:Estrogens; D007211:Indoles; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma; C016392:3,3'-diindolylmethane