PhD, New York University School of Medicine
Finding the epigenetic mechanisms behind arsenic-induced carcinogenesis
Arsenic (As) is a naturally occurring ubiquitous metalloid found in the Earth’s crust, sediments rich in organic matter as well as volcanic terranes. Areas of the world suffering most heavily include Bangladesh and West Bengal. In the 1960s and 1970s, international aids and governmental institutions initiated the digging of tube-wells in effort to provide alternatives for people suffering from low quality surface drinking water and related water-borne diseases. However, due to the lack of pre-testing for underground impurities, the hundreds of thousands of tube-wells providing arsenic contaminated drinking water became the sources of one of the most devastating mass poisoning in human history. However, the extent of arsenic contamination is not localized to these two particular regions. In fact, alarming levels found in the French Mediterranean costal areas, United States, China, Ghana, and Mexico illustrate the wide-ranging presence of this hazardous carcinogen around the globe. Beginning in the 1990s, arsenic elicited health concerns began to gain recognition as a global public health issue; today a staggering amount of nearly 200 million people are exposed to unacceptible levels of this class one human carcinogen. Although the World Health Organization’s recommended limit is 10 parts per billion (ppb), arsenic concentrations documented in approximately 70 countries can range any where from 0.5 to 5000 ppb. Inorganic arsenic has been identified as the causal agent in lung, bladder, liver, and prostate cancers. Although arsenic has long been known to induce toxicity and carcinogenicity via epigenetic mechanisms, alteration in histone gene expression is scarcely studied. As a critical protein for canonical histone pre-mRNA processing, the loss of Stem Loop Binding Protein (SLBP) can lead to malignant cellular transformation, a precursor for tumorigenesis. The domino effect of changes in SLBP can lead to alterations in the activation of more than 2000 highly active genes in the body. Thus, understanding the role of arsenic in regulating SLBP may bring new insights for arsenic-related cancer therapies.
Abstract: Exposure to inorganic arsenic is associated with numerous adverse health outcomes, with susceptibility differing by sex. While evidence from in vitro studies suggests that arsenic alters post-translational histone modifications (PTHMs), evidence in humans is limited.The objectives were to determine: 1) if arsenic exposure is associated with global (%) levels of PTHMs: H3K36me2, H3K36me3, and H3K79me2 in a sex-dependent manner and 2) if %PTHMs are stable when arsenic exposure is reduced.We examined associations between arsenic, measured in blood and urine, and %PTHMs in peripheral blood mononuclear cells from 317 participants enrolled in the Bangladesh Folic Acid and Creatine Trial (FACT). We also examined the stability of %PTHMs after the use of arsenic-removal water filters (n = 60).Associations between natural log-transformed (ln) urinary arsenic, adjusted for creatinine (uAsCr), and %H3K36me2 differed significantly between men and women (p = 0.01). Ln-uAsCr was positively associated with %H3K36me2 in men (β = 0.12; 95% CI: 0.01, 0.23, p = 0.03), but was negatively associated with %H3K36me2 in women (β = -0.05; 95% CI: -0.12, 0.02, p = 0.19). The patterns of associations with blood arsenic were similar. On average, water filter use was also associated with reductions in %H3K36me2 (p < 0.01), but this did not differ significantly by sex. Arsenic was not significantly associated with %H3K36me3 or %H3K79me2 in men or women.Arsenic exposure was associated with %H3K36me2 in a sex-specific manner, but was not associated with %H3K36me3 or %H3K79me2. Additional studies are needed to assess changes in %H3K36me2 after arsenic removal.
Pub.: 12 Mar '16, Pinned: 28 Jun '17
Abstract: The replication-dependent histone genes are the only metazoan genes whose messenger RNA (mRNA) does not terminate with a poly(A) tail at the 3'-end. Instead, the histone mRNAs display a stem-loop structure at their 3'-end. Stem-loop-binding protein (SLBP) binds the stem-loop and regulates canonical histone mRNA metabolism. Here we report that exposure to arsenic, a carcinogenic metal, decreased cellular levels of SLBP by inducing its proteasomal degradation and inhibiting SLBP transcription via epigenetic mechanisms. Notably, arsenic exposure dramatically increased polyadenylation of canonical histone H3.1 mRNA possibly through down-regulation of SLBP expression. The polyadenylated H3.1 mRNA induced by arsenic was not susceptible to normal degradation that occurs at the end of S phase, resulting in continued presence into mitosis, increased total H3.1 mRNA, and increased H3 protein levels. Excess expression of canonical histones have been shown to increase sensitivity to DNA damage as well as increase the frequency of missing chromosomes and induce genomic instability. Thus, polyadenylation of canonical histone mRNA following arsenic exposure may contribute to arsenic-induced carcinogenesis.
Pub.: 01 Oct '14, Pinned: 28 Jun '17
Abstract: Concerns for arsenic exposure are not limited to toxic waste sites and massive poisoning events. Chronic exposure continues to be a major public health problem worldwide, affecting hundreds of millions of persons.We reviewed recent information on worldwide concerns for arsenic exposures and public health to heighten awareness of the current scope of arsenic exposure and health outcomes and the importance of reducing exposure, particularly during pregnancy and early life.We synthesized the large body of current research pertaining to arsenic exposure and health outcomes with an emphasis on recent publications.Locations of high arsenic exposure via drinking water span from Bangladesh, Chile, and Taiwan to the United States. The U.S. Environmental Protection Agency maximum contaminant level (MCL) in drinking water is 10 µg/L; however, concentrations of > 3,000 µg/L have been found in wells in the United States. In addition, exposure through diet is of growing concern. Knowledge of the scope of arsenic-associated health effects has broadened; arsenic leaves essentially no bodily system untouched. Arsenic is a known carcinogen associated with skin, lung, bladder, kidney, and liver cancer. Dermatological, developmental, neurological, respiratory, cardiovascular, immunological, and endocrine effects are also evident. Most remarkably, early-life exposure may be related to increased risks for several types of cancer and other diseases during adulthood.These data call for heightened awareness of arsenic-related pathologies in broader contexts than previously perceived. Testing foods and drinking water for arsenic, including individual private wells, should be a top priority to reduce exposure, particularly for pregnant women and children, given the potential for life-long effects of developmental exposure.
Pub.: 06 Mar '13, Pinned: 28 Jun '17