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

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.

Keywords: Arsenic; F2; Gestational exposure; Hepatic tumor; Multigenerational.

Fig. 1

Late-onset changes in gene expression in the non-tumor-bearing livers of F1 male mice gestationally exposed to arsenic. Expression of four genes in the livers of control and gestationally arsenic-exposed mice was measured by real-time PCR at 6, 49, and 74 weeks of age and normalized to the expression of cyclophilin B (CPB). The graphs show the ratio of expression in the arsenic group normalized to expression in the control group. The data shown are the means ± S.E. (n = 11 for 6 w, n = 4 for 49 w, n = 8 for 74 w). * significant difference between the two groups at p < 0.05 (21)

Fig. 2

Increased Line-1 RNA expression in the livers of adult F1 male mice gestationally exposed to arsenic. Expression of ORF1 and ORF2 in normal adult livers, normal tissue from tumor-bearing livers, and tumor tissue from tumor-bearing livers were measured by real-time PCR and normalized to the expression of CPB. Results are reported as means ± S.E. (n = 6). * significant difference between the two groups at p < 0.05 (21)

Fig. 3

Possible actions of gestationally exposed arsenic in the hepatic tumorigenesis in F1 mice (22)

Fig. 4

Increase in the tumor incidence in the F2 male offspring born to arsetite-F1 males but not to ansenite-F1 females. The F2 mice were macroscopically examined for hepatic tumors at 75-82 weeks of age in an age-matched manner (23). The difference between the tumor incidences in the two groups was analyzed by chi-square test