Reference SummaryWaalkes MP, Carcinogenesis 2004 Jan;25(1):133-41

Title

 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.

Authors

 Waalkes MP; Ward JM; Diwan BA

Journal

 Carcinogenesis

Volume

 25

Issue

 1

Year

 2004

Pages

 133-41

Abstract

 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.

Links

 J:87703 – MGI References
14514661 – National Library of Medicine/PubMed

Strain Notes

Strain Note
C3H/HeNCr Survival slightly decreased in males in following treatment group. ( 85 ppm arsenic + acetone promotion)

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C3H/HeNCr Adipose tissue lipoma Kidney

observed
C3H/HeNCr Adipose tissue lipoma Intestine - Small Intestine

observed
C3H/HeNCr Adrenal gland - Cortex adenoma Adrenal gland - Cortex

8.3 - 37.5
C3H/HeNCr Adrenal gland - Cortex adenoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Adrenal gland - Cortex

0 - 30
C3H/HeNCr Adrenal gland - Cortex adenoma
  • sodium arsenite
 Adrenal gland - Cortex

0 - 71
C3H/HeNCr Adrenal gland - Cortex adenoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Adrenal gland - Cortex

4.5 - 65
C3H/HeNCr Adrenal gland - Cortex carcinoma Adrenal gland - Cortex

0
C3H/HeNCr Adrenal gland - Cortex carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Adrenal gland - Cortex

0 - 4.2
C3H/HeNCr Adrenal gland - Cortex carcinoma
  • sodium arsenite
 Adrenal gland - Cortex

0
C3H/HeNCr Adrenal gland - Cortex carcinoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Adrenal gland - Cortex

0
C3H/HeNCr Adrenal gland - Medulla pheochromocytoma
  • sodium arsenite
 Adrenal gland - Medulla

4.8
C3H/HeNCr Blood vessel hemangioma Liver

observed
C3H/HeNCr Blood vessel hemangioma Uterus

observed
C3H/HeNCr Blood vessel hemangioma Ovary

observed
C3H/HeNCr Blood vessel hemangioma Leg

observed
C3H/HeNCr Blood vessel hemangioma Oviduct

observed
C3H/HeNCr Blood vessel hemangioma Heart

observed
C3H/HeNCr Blood vessel hemangioma Kidney

observed
C3H/HeNCr Blood vessel hemangioma Intestine - Small Intestine

observed
C3H/HeNCr Blood vessel hemangioma Spleen

observed
C3H/HeNCr Blood vessel hemangiosarcoma Liver

observed
C3H/HeNCr Connective tissue - Fibroblast fibrosarcoma Preputial gland (male)

observed
C3H/HeNCr Connective tissue myxoma Uterus - Cervix

observed
C3H/HeNCr Eye - Harderian gland adenoma Eye - Harderian gland

observed
C3H/HeNCr Eye - Harderian gland carcinoma Eye - Harderian gland

observed
C3H/HeNCr Leukocyte lymphoma Leukocyte

observed
C3H/HeNCr Liver hepatoblastoma
  • sodium arsenite
 Liver

4.8
C3H/HeNCr Liver hepatocellular adenoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Liver

18 - 76
C3H/HeNCr Liver hepatocellular adenoma
  • sodium arsenite
 Liver

13 - 90
C3H/HeNCr Liver hepatocellular adenoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Liver

8.3 - 35
C3H/HeNCr Liver hepatocellular adenoma Liver

8.3 - 42
C3H/HeNCr Liver hepatocellular carcinoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Liver

9.1 - 33
C3H/HeNCr Liver hepatocellular carcinoma
  • sodium arsenite
 Liver

4.8 - 48
C3H/HeNCr Liver hepatocellular carcinoma Liver

4.2 - 12.5
C3H/HeNCr Liver hepatocellular carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Liver

8.3 - 8.7
C3H/HeNCr Liver hepatocellular tumor
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Liver

27 - 86
C3H/HeNCr Liver hepatocellular tumor
  • sodium arsenite
 Liver

19 - 90
C3H/HeNCr Liver hepatocellular tumor
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Liver

12.5 - 39
C3H/HeNCr Liver hepatocellular tumor Liver

12.5 - 50
C3H/HeNCr Lung adenoma Lung

4.2 - 17
C3H/HeNCr Lung adenoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Lung

4.2 - 8.7
C3H/HeNCr Lung adenoma
  • sodium arsenite
 Lung

8.7 - 26
C3H/HeNCr Lung adenoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Lung

9.1 - 43
C3H/HeNCr Lung carcinoma Lung

0
C3H/HeNCr Lung carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Lung

4.2 - 4.3
C3H/HeNCr Lung carcinoma
  • sodium arsenite
 Lung

0 - 4.8
C3H/HeNCr Lung carcinoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Lung

0 - 9.5
C3H/HeNCr Lung tumor
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Lung

8.3 - 13
C3H/HeNCr Lung tumor
  • sodium arsenite
 Lung

8.7 - 30
C3H/HeNCr Lung tumor
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Lung

18 - 43
C3H/HeNCr Lung tumor Lung

4.2 - 17
C3H/HeNCr Mammary gland adenocarcinoma Mammary gland

observed
C3H/HeNCr Melanocyte melanoma Uterus - Cervix

observed
C3H/HeNCr Mesodermal cell/mesoblast sarcoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Skin

4.5
C3H/HeNCr Mesodermal cell/mesoblast sarcoma Skin

8.3
C3H/HeNCr Mesodermal cell/mesoblast sarcoma Leg

observed
C3H/HeNCr Mesodermal cell/mesoblast sarcoma Liver

observed
C3H/HeNCr Mesodermal cell/mesoblast sarcoma Peritoneum

observed
C3H/HeNCr Mesodermal cell/mesoblast squamous cell sarcoma Forestomach

observed
C3H/HeNCr Muscle - Smooth leiomyoma Uterus

observed
C3H/HeNCr Ovary adenoma
  • sodium arsenite
 Ovary

17 - 19
C3H/HeNCr Ovary adenoma Ovary

0
C3H/HeNCr Ovary adenoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Ovary

0
C3H/HeNCr Ovary adenoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Ovary

19 - 23
C3H/HeNCr Ovary carcinoma Ovary

0
C3H/HeNCr Ovary carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Ovary

0
C3H/HeNCr Ovary carcinoma
  • sodium arsenite
 Ovary

0 - 4.3
C3H/HeNCr Ovary carcinoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Ovary

0
C3H/HeNCr Ovary tumor Ovary

0
C3H/HeNCr Ovary tumor
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Ovary

0
C3H/HeNCr Ovary tumor
  • sodium arsenite
 Ovary

19 - 22
C3H/HeNCr Ovary tumor
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Ovary

19 - 23
C3H/HeNCr Oviduct adenoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Oviduct

4.5
C3H/HeNCr Oviduct hyperplasia Oviduct

12.5
C3H/HeNCr Oviduct hyperplasia
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Oviduct

12.5
C3H/HeNCr Oviduct hyperplasia
  • sodium arsenite
 Oviduct

35 - 48
C3H/HeNCr Oviduct hyperplasia
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Oviduct

32 - 43
C3H/HeNCr Renal pelvis papilloma Renal pelvis

observed
C3H/HeNCr Skin squamous cell carcinoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Skin

4.3
C3H/HeNCr Thyroid gland adenoma Thyroid gland

observed
C3H/HeNCr Ureter transitional cell carcinoma Ureter

observed
C3H/HeNCr Uterus adenoma Uterus

0
C3H/HeNCr Uterus adenoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Uterus

0
C3H/HeNCr Uterus adenoma
  • sodium arsenite
 Uterus

4.3 - 4.8
C3H/HeNCr Uterus adenoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Uterus

4.5 - 4.8
C3H/HeNCr Uterus hyperplasia - cystic Uterus

25
C3H/HeNCr Uterus hyperplasia - cystic
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Uterus

29
C3H/HeNCr Uterus hyperplasia - cystic
  • sodium arsenite
 Uterus

61 - 67
C3H/HeNCr Uterus hyperplasia - cystic
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Uterus

68 - 71
C3H/HeNCr Uterus lesion Uterus

25
C3H/HeNCr Uterus lesion
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Uterus

29
C3H/HeNCr Uterus lesion
  • sodium arsenite
 Uterus

65 - 71
C3H/HeNCr Uterus lesion
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 Uterus

73 - 76
C3H/HeNCr (Unspecified organ) adenoma
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 (Unspecified organ)

observed
C3H/HeNCr (Unspecified organ) tumor
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 (Unspecified organ)

observed
C3H/HeNCr (Unspecified organ) tumor (Unspecified organ)

observed
C3H/HeNCr (Unspecified organ) tumor
  • sodium arsenite
 (Unspecified organ)

observed
C3H/HeNCr (Unspecified organ) tumor
  • sodium arsenite
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
 (Unspecified organ)

observed