Fetal Onset of Aberrant Gene Expression Relevant to Pulmonary Carcinogenesis in Lung Adenocarcinoma Development Induced by In Utero Arsenic Exposure

Abstract

Arsenic is a human pulmonary carcinogen. Our work indicates that in utero arsenic exposure in mice can induce or initiate lung cancer in female offspring. To define early molecular changes, pregnant C3H mice were given 85 ppm arsenic in drinking water from days 8 to 18 of gestation and expression of selected genes in the fetal lung or in lung tumors developing in adults was examined. Transplacental arsenic exposure increased estrogen receptor-alpha (ER-alpha) transcript and protein levels in the female fetal lung. An overexpression of various estrogen-regulated genes also occurred, including trefoil factor-3, anterior gradient-2, and the steroid metabolism genes 17-beta-hydroxysteroid dehydrogenase type 5 and aromatase. The insulin growth factor system, which can be influenced by ER and has been implicated in the pulmonary oncogenic process, was activated in fetal lung after gestational arsenic exposure. In utero arsenic exposure also induced overexpression of alpha-fetoprotein, epidermal growth factor receptor, L-myc, and metallothionein-1 in fetal lung, all of which are associated with lung cancer. Lung adenoma and adenocarcinoma from adult female mice exposed to arsenic in utero showed widespread, intense nuclear ER-alpha expression. In contrast, normal adult lung and diethylnitrosamine-induced lung adenocarcinoma showed little evidence of ER-alpha expression. Thus, transplacental arsenic exposure at a carcinogenic dose produced aberrant estrogen-linked pulmonary gene expression. ER-alpha activation was specifically associated with arsenic-induced lung adenocarcinoma and adenoma but not with nitrosamine-induced lung tumors. These data provide evidence that arsenic-induced aberrant ER signaling could disrupt early life stage genetic programing in the lung leading eventually to lung tumor formation much later in adulthood.

Aberrant DNA methylation and gene expression in livers of newborn mice transplacentally exposed to a hepatocarcinogenic dose of inorganic arsenic

“…The expression of HSD17β5 dehydrogenase, an enzyme catalyzing the transformation of 4-androstenedione (4-dione) into testosterone, was also decreased. These changes are consistent with male liver feminization and a role of aberrant estrogen signaling seen in our series of transplacental arsenic carcinogenesis studies (Waalkes et al, 2004b(Waalkes et al, , 2006aLiu et al, 2006Shen et al, 2007).…”

Arsenic in Drinking Water and Risk of Urinary Tract Cancer: A Follow-up Study from Northeastern Taiwan

“…We found that those who started drinking well water from birth, still drank at enrollment, and drank it for long period were at a significantly increased risk of urinary cancer, especially urothelial carcinoma. Evidence from experimental studies (19)(20)(21)(22) showed that early-life exposure to arsenic may increase the health risks during early childhood and later in life. Up to date, only one ecologic study (23) conducted in Chile showed that exposure to arsenic in drinking water during early childhood or in utero was associated with an increased mortality in young adults from both malignant and nonmalignant lung diseases.…”

Prevention of arsenic-mediated reproductive toxicity in adult female rats by high protein diet

“…The detrimental impact of arsenic also includes dysfunction of endocrine (Tseng et al, 2000) and reproductive systems (Singh & Rana, 2007). Limited evidence suggests that adverse human reproductive effects of arsenic may include higher risk of low birth weight, spontaneous abortion, preeclampsia, congenital malformation, infant mortality (Ahmad et al, 2001) and carcinoma incidence to the new born (Shen et al, 2007). In experimental rodent model, arsenic has been reported to produce toxic effects on female reproductive system (Chattopadhyay et al, 1999).…”