Tumor-augmenting effects of gestational arsenic exposure on F1 and F2 in mice

Keiko Nohara,Shota Takumi,Kazuyuki Okamura,Junya Matsushita,Takehiro Suzuki

doi:10.1186/s41021-016-0069-1

Abstract

The consequences of early-life exposure to chemicals in the environment are emerging concerns. Chronic exposure to naturally occurring inorganic arsenic has been known to cause various adverse health effects, including cancers, in humans. On the other hand, animal studies by Dr. M. Waalkes’ group reported that arsenite exposure of pregnant F0 females, only from gestational day 8 to 18, increased hepatic tumors in the F1 (arsenite-F1) males of C3H mice, whose males tend to develop spontaneous hepatic tumors later in life. Since this mice model illuminated novel unidentified consequences of arsenic exposure, we wished to further investigate the background mechanisms. In the same experimental model, we identified a variety of factors that were affected by gestational arsenic exposure, including epigenetic and genetic changes, as possible constituents of multiple steps of late-onset hepatic tumor augmentation in arsenite-F1 males. Furthermore, our study discovered that the F2 males born to arsenite-F1 males developed hepatic tumors at a significantly higher rate than the control F2 males. The results imply that the tumor augmenting effect is inherited by arsenite-F2 males through the sperm of arsenite-F1. In this article, we summarized our studies on the consequences of gestational arsenite exposure in F1 and F2 mice to discuss novel aspects of biological effects of gestational arsenic exposure.

Highlights

Arsenic is widely distributed in the environment
Since inorganic arsenite and arsenate have been shown to be metabolized into organic arsenic compounds having higher toxicity [11], we investigated mutagenicity of inorganic arsenite in transgenic mice developed for detecting in vivo mutations, as described later [12]
Our studies showed that gestational arsenite exposure induces late-onset gene expression changes in normal livers and expansion of tumors having epigenetic and genetic changes in the F1 males of C3H mice

Summary

Introduction

Arsenic is widely distributed in the environment. Occupational exposure to various forms of arsenic compounds, as well as chronic exposure to naturally occurring background arsenic have been shown to cause serious health problems, including skin lesions, cardiovascular diseases, neuronal disorders, and cancers, in many areas in the world [1,2,3,4,5,6]. We summarize our studies on the cancer augmenting effects of gestational arsenite exposure in arsenite-F1 and arsenite-F2 males and discuss their mechanisms, including epigenetics and mutation. Demonstrated that administration of pregnant C3H mice with drinking water containing 42.5 or 85 ppm sodium arsenite only from day 8 to 18 of gestation significantly augmented hepatic tumor incidence in the male offspring at 74 weeks of age.

Results

Conclusion