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Urogenital Carcinogenesis in Female CD1 Mice Induced by In utero Arsenic Exposure Is Exacerbated by Postnatal Diethylstilbestrol Treatment

¹ Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; ² National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland; ³ Data Management Services, Inc., National Cancer Institute at Frederick; and ⁴ Basic Research Program, Science Applications International Corporation at Frederick, National Cancer Institute at Frederick, Frederick, Maryland

Requests for reprints: Michael P. Waalkes, Inorganic Carcinogenesis Section, National Cancer Institute at National Institute of Environmental Health Sciences, P.O. Box 12233, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709. Phone: 919-541-2328; Fax: 919-541-3970; E-mail: waalkes{at}niehs.nih.gov.

Transplacental inorganic arsenic carcinogenicity, together with postnatal exposure to diethylstilbestrol or tamoxifen, was studied. Pregnant CD1 mice received 85 ppm arsenic in the drinking water from gestation days 8 to 18 and were allowed to give birth. Groups (n = 35) of female offspring were injected s.c. on postpartum days 1 through 5 with diethylstilbestrol (2 µg/pup/d) or tamoxifen (10 µg/pup/d) and observed for 90 weeks. Arsenic alone induced some urogenital system tumors, including mostly benign tumors of the ovary and uterus, and adrenal adenoma. Diethylstilbestrol alone induced some tumors (primarily cervical) but when given after in utero arsenic, it greatly enhanced urogenital tumor incidence, multiplicity, and progression. For instance, compared with the incidence of urogenital malignancies in the control (0%), arsenic alone (9%), and diethylstilbestrol alone (21%) groups, arsenic plus diethylstilbestrol acted synergistically, inducing a 48% incidence of malignant urogenital tumors. Of the urogenital tumors induced by arsenic plus diethylstilbestrol, 80% were malignant, and 55% were multiple site. Arsenic plus diethylstilbestrol increased ovarian, uterine, and vaginal tumors, and urinary bladder proliferative lesions, including three transitional cell carcinomas. Tamoxifen alone did not increase urogenital tumors or affect arsenic-induced neoplasia but did increase arsenic-induced uroepithelial proliferative lesions. Uterine and bladder carcinoma induced by arsenic plus diethylstilbestrol greatly overexpressed estrogen receptor- (ER-) and pS2, an estrogen-regulated gene. In neonatal uteri, prenatal arsenic increased ER- expression and enhanced estrogen-related gene expression induced by postnatal diethylstilbestrol. Thus, arsenic acts with estrogens to enhance production of female mouse urogenital cancers. (Cancer Res 2006; 66(3): 1337-45)

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