Faculty Bibliography

Consumption of essential metals is needed for function of certain protein to maintain normal cell integrity. Incorporation and excretion of these metals are governed by the cells, but changes in environmental levels of metals can cause stress. There are areas in which the ambient environment contains non-essential metals that function as toxicants, which alter metal homeostasis thus causing oxidative stress and epigenetic alterations. Ambient air and water, as well as food items in poorly protected areas contain toxic metals, such as arsenic, cadmium, and chromium. Often the exposure to these common metal pollutants is associated with inflammatory diseases and carcinogenesis. However, epidemiology studies and animal experiments demonstrate these metals affect fertility spermatogenesis, sperm concentration, sperm motility, oocyte integrity via epigenetic changes, and contribute to gestational complications. In this review, we present a comprehensive summary of studies demonstrating the detrimental effects of exposure to these metals commonly found in ambient environment on the reproductive health of both males and females.

Arsenic, a class I human carcinogen, is ubiquitously found throughout the environment and around the globe, posing a great public health concern. Notably, Bangladesh and regions of West Bengal have been found to have high levels (0.5-4600 μg/L) of arsenic drinking water contamination, and approximately 50 million of the world's 200 million people chronically exposed to arsenic in Bangladesh alone. This study was carried out to examine genome-wide gene expression changes in individuals chronically exposed to arsenic-contaminated drinking water. Our study population includes twenty-nine Bangladeshi female participants with urinary arsenic levels ranging from 22.32 to 1828.12 μg/g creatinine. RNA extracted from peripheral blood mononuclear cells (PBMCs) were evaluated using RNA-Sequencing analysis. Our results indicate that a total of 1,054 genes were significantly associated with increasing urinary arsenic levels (FDR p < 0.05), which include 418 down-regulated and 636 up-regulated genes. Further Ingenuity Pathway Analysis revealed potential target genes (DAPK1, EGR2, APP), microRNAs (miR-155, -338, -210) and pathways (NOTCH signaling pathway) related to arsenic carcinogenesis. The selection of female-only participants provides a homogenous study population since arsenic has significant sex dependent effects, and the wide exposure range provides new insight for key gene expression changes that correlate with increasing urinary arsenic levels.

Arsenic contamination impacts hundreds of millions of people in the world. Arsenic is a well-established human carcinogen and has been shown to cause skin, lung, bladder, liver, prostate and kidney cancers, in humans. Mechanisms that underlie arsenic-mediated carcinogenesis, including epigenetic alterations, remain largely unknown. Human exposure to Arsenic is reviewed, and the mechanisms of its acute and chronic toxicity and mechanisms of its carcinogenesis in humans are discussed. Arsenic is one of the few metals that is metabolized in vivo, and Arsenic methylation and how this results in a shorter half-life in vivo are discussed. A review of recent findings that Arsenic causes loss in the cellular levels of Stem Loop Binding Protein (SLBP) resulting in polyadenylation of canonical histones (H3.1) as a default, increasing levels of H3.1 protein outside of S-Phase. Malignant cell transformation is induced by knockdown of SLBP and by overexpression of polyadenylated H3.1. Arsenic induced polyadenylation of H3.1 causes enhanced levels of H3.1 protein displacing H3.3 protein from its cellular binding sites, since the two proteins differ by only 5 amino acids. Knockdown of H3.3 alone can induce carcinogenesis, and therefore displacement of functional H3.3 protein by increased H3.1 protein, is likely a mechanism of arsenic carcinogenesis.

Chromium (Cr) is a naturally occurring metallic element found in the Earth's crust. While trivalent chromium ([Cr(III)] is considered non-carcinogenic, hexavalent chromium [Cr(VI)] has long been established as an IARC class I human carcinogen, known to induce cancers of the lung. Current literature suggests that Cr(VI) is capable of inducing carcinogenesis through both genetic and epigenetic mechanisms. Although much has been learned about the molecular etiology of Cr(VI)-induced lung carcinogenesis, more remains to be explored. In particular, the explicit epigenetic alterations induced by Cr(VI) in lung cancer including histone modifications and miRNAs, remain understudied. Through comprehensive review of available literature found between 1973 and 2019, this article provides a summary of updated understanding of the molecular mechanisms of Cr(VI)-carcinogenesis. In addition, this review identifies potential research gaps in the areas of histone modifications and miRNAs, which may prompt new niches for future research.

The special AT-rich DNA binding protein (SATB2) is a nuclear matrix-associated protein and an important transcription factor for biological development, gene regulation and chromatin remodeling. Aberrant regulation of SATB2 has been found to highly correlate with various types of cancers including lung, colon, prostate, breast, gastric and liver. Recent studies have revealed that a subset of small non-coding RNAs, termed microRNAs (miRNAs), are important regulators of SATB2 function. As post-transcriptional regulators, miRNAs have been found to have fundament importance maintaining normal cellular development. Evidence suggests that multiple miRNAs, including miR-31, miR-34, miR-182, miR-211, miR-599, are capable of regulating SATB2 in cancers of the lung, liver, colon and breast. This review examines the molecular functions of SATB2 and miRNAs in the text of cancer development and potential strategies for cancer therapy with a focus on systemic miRNA delivery.

Chromium is a pervasive environmental contaminant that is of great importance because of its toxicity. Hexavalent chromium is a classified group 1 carcinogen with multiple complex mechanisms by which it triggers cancer development. Increased levels of oxidative stress, chromosome breaks, and DNA-adduct formation are some of the major mechanisms by which C(VI) causes cellular damage. Trivalent chromium is another species of chromium that is described as a non-essential metal, and is used in nutritional supplementation. Evidence on nutritional benefit is conflicting which could suggest that humans absorb enough Cr(III) from diet alone, and that extra supplementation is not necessary. This review highlights the differences between Cr(VI) and Cr(III) from a chemical and toxicological perspective, describes short-comings in nutritional research of Cr(III), and explains the multiple mechanisms by which Cr(VI) is involved in the process of carcinogenesis.

Following a 1983 chromic acid (hexavalent chromium [CrVI]) spill from a Garfield, NJ electroplating plant, CrVI-contaminated water was found in a local firehouse basement in 1993. An ATSDR public health advisory was issued for the plant site in 2010, and from 2008-2015, fourteen residential properties have required remediation to address CrVI-contaminated dust in the basements. As part of the Community Outreach and Engagement Core of the NYU NIEHS Center, seventytwo Garfield residents aged 18-65 years, participated in a community survey with the goal of identifying concerns related to environmental and community health. Thirty-two percent responded that they 'didn't know' if they were exposed to chemicals or pollutants where they live. This finding suggests a limited awareness of environmental chemical exposures, chromium contamination and/or potential exposure to CrVI. Furthermore, toenail clippings were collected from forty-seven Garfield residents and analyzed for total chromium levels to assess potential long-term exposure. On average, residents living on/inside the contaminated plume area had higher total chromium levels in their toenail clippings than residents living outside the plume area. However, chromium levels for all participants were within the range of historical normal. This study highlights the value of partnerships between environmentally-impacted community's and academic scientists working together to identify potential contaminant exposures and address public health concerns through research and environmental health education.