Late-onset increases in oxidative stress and other tumorigenic activities and tumors with a Ha-ras mutation in the liver of adult male C3H mice gestationally exposed to arsenic.
Tumorigenesis is a complex process involving genetic, epigenetic, and metabolic alterations. Gestational arsenic exposure has been shown to increase hepatic tumors in adult male offspring of C3H mice, which spontaneously develop hepatic tumors often harboring activating Ha-ras mutation. We explored tumor-promoting changes by gestational arsenic exposure with a focus on Ha-ras mutation and gene expression changes. The results of this study demonstrated that gestational arsenic exposure particularly increased hepatic tumors with a C61A Ha-ras mutation. Real-time PCR analyses on the adult normal livers showed that two genes (Creld2, Slc25a30), whose expression are induced by endoplasmic reticulum stress and cellular oxidative stress, respectively, were significantly upregulated and two genes (Fabp4, Ell3), whose products are involved in lipid efflux and apoptosis, respectively, were significantly downregulated more than twofold by gestational arsenic exposure compared with control mice. The expression changes in the four genes were shown to be late-onset events and to some extent to be associated with corresponding histone modifications, and not with DNA methylation changes. The gene expression changes suggested alterations in lipid metabolism and associated oxidative stress augmentation. Consistently, expression of an oxidative-stress-inducible gene heme oxygenase-1 (HO-1) was upregulated in the livers of the arsenic group. We also found increased expression of retrotransposon L1 mRNA in the tumor-bearing livers of the arsenic group in comparison with control mice. These results suggested that gestational arsenic exposure induces tumor-augmenting changes, including oxidative stress and L1 activation, in a late-onset manner, which would particularly promote tumorigenic expansion of cells with a C61A Ha-ras mutation.
Center for Environmental Health Sciences, National Institute for Environmental Studies, Tsukuba 305-8506, Japan. keikon@nies.go.jp
Keiko
K
Nohara
Yukiyo
Y
Tateishi
Takehiro
T
Suzuki
Kazuyuki
K
Okamura
Hikari
H
Murai
Shota
S
Takumi
Fumihiko
F
Maekawa
Noriko
N
Nishimura
Masuko
M
Kobori
Takaaki
T
Ito
D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D047369:Chromatin Immunoprecipitation; D005260:Female; D011905:Genes, ras; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D018384:Oxidative Stress; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction
D002273:Carcinogens; D001151:Arsenic