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Response to “Comment on ‘Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice’”

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      Transplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice.

      Arsenic is a known human carcinogen, but development of rodent models of inorganic arsenic carcinogenesis has been problematic. Since gestation is often a period of high sensitivity to chemical carcinogenesis, we performed a transplacental carcinogenicity study in mice using inorganic arsenic. Groups (n = 10) of pregnant C3H mice were given drinking water containing sodium arsenite (NaAsO(2)) at 0 (control), 42.5, and 85 ppm arsenite ad libitum from day 8 to 18 of gestation. These doses were well tolerated and body weights of the dams during gestation and of the offspring subsequent to birth were not reduced. Dams were allowed to give birth, and offspring were weaned at 4 weeks and then put into separate gender-based groups (n = 25) according to maternal exposure level. The offspring received no additional arsenic treatment. The study lasted 74 weeks in males and 90 weeks in females. A complete necropsy was performed on all mice and tissues were examined by light microscopy in a blind fashion. In male offspring, there was a marked increase in hepatocellular carcinoma incidence in a dose- related fashion (control, 12%; 42.5 ppm, 38%; 85 ppm, 61%) and in liver tumor multiplicity (tumors per liver; 5.6-fold over control at 85 ppm). In males, there was also a dose-related increase in adrenal tumor incidence and multiplicity. In female offspring, dose-related increases occurred in ovarian tumor incidence (control, 8%; 42.5 ppm, 26%; 85 ppm, 38%) and lung carcinoma incidence (control, 0%; 42.5 ppm, 4%; 85 ppm, 21%). Arsenic exposure also increased the incidence of proliferative lesions of the uterus and oviduct. These results demonstrate that oral inorganic arsenic exposure, as a single agent, can induce tumor formation in rodents and establishes inorganic arsenic as a complete transplacental carcinogen in mice. The development of this rodent model of inorganic arsenic carcinogenesis has important implications in defining the mechanism of action for this common environmental carcinogen. Copyright 2003 Elsevier Science (USA)
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        Induction of tumors of the liver, lung, ovary and adrenal in adult mice after brief maternal gestational exposure to inorganic arsenic: promotional effects of postnatal phorbol ester exposure on hepatic and pulmonary, but not dermal cancers.

        Arsenic is a recognized human carcinogen and development of rodent models remains a critically important research objective. Since gestation can be a period of high sensitivity to chemical carcinogenesis, we have performed a series of transplacental carcinogenicity studies in mice with inorganic arsenic. In this study, groups of pregnant C3H mice received drinking water containing sodium arsenite (NaAsO2) at 0, 42.5 and 85 p.p.m. arsenic ad libitum from days 8 to 18 of gestation. These doses of arsenic were well tolerated. Dams delivered normally and at weaning (4 weeks) offspring were randomly put into groups (n = 25) of males or females according to maternal dose. In an attempt to promote skin cancers initiated by transplacental arsenic, duplicate groups of control or arsenic exposed offspring were topically exposed to 12-O-tetradecanoyl phorbol-13-acetate (TPA; 2 micro g/0.1 ml acetone, twice/week) from 4 to 25 weeks of age. Irrespective of TPA exposure, male offspring showed arsenic-induced dose-related increases in hepatocellular carcinoma incidence and multiplicity, as well as increases in adrenal tumor incidence and multiplicity. In female offspring, an increase in epithelial ovarian tumors occurred with arsenic exposure regardless of TPA exposure. Females also showed pre-neoplastic lesions of the reproductive tract, including hyperplasia of the uterus and oviduct, after arsenic but independent of TPA exposure. Although TPA had no effect on skin tumors, it promoted arsenic initiated liver tumors in females and lung tumors in both sexes. Thus, inorganic arsenic, as a single agent, can consistently act as a complete transplacental carcinogen in mice, inducing tumors at multiple sites, and as a tumor initiator in some tissues. Skin tumors were not initiated by arsenic in mouse fetuses possibly indicating tissue-specific mechanisms of action. This study indicates that gestation is a period of high sensitivity to arsenic carcinogenesis.
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          Urogenital carcinogenesis in female CD1 mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment.

          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 microg/pup/d) or tamoxifen (10 microg/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-alpha (ER-alpha) and pS2, an estrogen-regulated gene. In neonatal uteri, prenatal arsenic increased ER-alpha expression and enhanced estrogen-related gene expression induced by postnatal diethylstilbestrol. Thus, arsenic acts with estrogens to enhance production of female mouse urogenital cancers.
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            Author and article information

            Affiliations
            National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina USA
            Author notes
            []Address correspondence to H.H-C. Yao, National Institute of Environmental Health Sciences, 111 T.W. Alexander Dr., Mail Drop C4-10, Research Triangle Park, NC 27709 USA. E-mail: humphrey.yao@ 123456nih.gov
            Journal
            Environ Health Perspect
            Environ. Health Perspect
            EHP
            Environmental Health Perspectives
            National Institute of Environmental Health Sciences
            0091-6765
            1552-9924
            1 March 2016
            March 2016
            : 124
            : 3
            : A46-A47
            26930461
            4786993
            ehp.1511181
            10.1289/ehp.1511181

            Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

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