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

Abstract

Our prior work showed that brief exposure of pregnant C3H mice to inorganic arsenic-induced hepatocellular carcinoma (HCC) formation in adult male offspring. The current study examined the early hepatic events associated with this oncogenic transformation. Pregnant mice were exposed to a known carcinogenic dose of arsenic (85 ppm) in the drinking water from gestation days 8 to 18. The dams were allowed to give birth and liver samples from newborn males were analyzed for arsenic content, global DNA methylation and aberrant expression of genes relevant to the carcinogenic process. Arsenic content in newborn liver reached 57 ng/g wet weight, indicating arsenic had crossed the placenta, reached the fetal liver and that significant amounts remained after birth. Global methylation status of hepatic DNA was not altered by arsenic in the newborn. However, a significant reduction in methylation occurred globally in GC-rich regions. Microarray and real-time RT-PCR analysis showed that arsenic exposure enhanced expression of genes encoding for glutathione production and caused aberrant expression of genes related to insulin growth factor signaling pathways and cytochrome P450 enzymes. Other expression alterations observed in the arsenictreated male mouse newborn liver included the overexpression of cdk-inhibitors and stress response genes including increased expression of metallothionein-1 and decreased expression of betainehomocysteine methyltransferase and thioether S-methyltransferase. Thus, transplacental exposure to arsenic at a hepatocarcinogenic dose induces alterations in DNA methylation and a complex set of aberrant gene expressions in the newborn liver, a target of arsenic carcinogenesis.

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.…”

Inuteroarsenic exposure and epigenome-wide associations in placenta, umbilical artery, and human umbilical vein endothelial cells

“…In the analysis that was unadjusted for cellular composition, one CpG loci (cg26587014) located in chromosome 19 and not annotated to any gene was differentially methylated in arterial tissue in relation to arsenic exposure using a Bonferroni threshold for statistical significance (P < 1.33 £ 10 ¡7 ). Controlling for the false discovery rate at 5% (q-value < 0.05) revealed 2,105 CpGs that were differentially methylated relative to log 2 -transformed maternal drinking water arsenic.…”

“…17,18 Therefore, it is postulated that epigenomic regulation including, but not limited to, DNA methylation is a potential mechanism of arsenic induced carcinogenesis and latent disease risk. 2,19,20 Other likely interacting mechanisms of early life exposure to arsenic and latent disease risk include the development of cancer stem cells and perturbations of immune function. 2 Several human studies have evaluated the impact of prenatal arsenic exposure on the cord blood and whole blood epigenome.…”

Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood

“…9 While it is not fully understood how early life exposure to arsenic would lead to increased susceptibility to disease later in life, experimental studies have shown that in utero exposure to arsenic alters DNA methylation in offspring. [10][11][12][13][14] There is also evidence from epidemiological studies that arsenic exposure from drinking water alters DNA methylation in whole blood collected in adults. [15][16][17] Recently, our group showed that maternal exposure Prenatal arsenic exposure is associated with increased risk of disease in adulthood.…”