Faculty Bibliography

BACKGROUND:Economic and social marginalization among American Indians and Alaska Natives (AI/ANs) results in higher chronic disease prevalence. Potential causal associations between toxic environmental exposures and adverse health outcomes within AI/AN communities are not well understood. OBJECTIVES/OBJECTIVE:This review examines epidemiological literature on exposure to toxicants and associated adverse health outcomes among AI/AN populations. METHODS:PubMed, Embase, Cochrane, Environment Complete, Web of Science Plus, DART, and ToxLine were searched for English-language articles. The following data were extracted: lead author's last name, publication year, cohort name, study location, AI/AN tribe, study initiation and conclusion, sample size, primary characteristic, environmental exposure, health outcomes, risk estimates, and covariates. RESULTS:About 31 articles on three types of environmental exposures met inclusion criteria: persistent organic pollutants (POPs), heavy metals, and open dumpsites. Of these, 17 addressed exposure to POPs, 10 heavy metal exposure, 2 exposure to both POPs and heavy metals, and 2 exposure to open dumpsites. Studies on the Mohawk Nation at Akwesasne; Yupik on St. Lawrence Island, Alaska; Navajo Nation; Gila River Indian Community; Cheyenne River Sioux; 197 Alaska Native villages; and 13 tribes in Arizona, Oklahoma, North Dakota, and South Dakota that participated in the Strong Heart Study support associations between toxicant exposure and various chronic conditions including cardiovascular conditions, reproductive abnormalities, cancer, autoimmune disorders, neurological deficits, and diabetes. DISCUSSION/CONCLUSIONS:The complex interplay of environmental and social factors in disease etiology among AI/ANs is a product of externally imposed environmental exposures, systemic discrimination, and modifiable risk behaviors. The connection between environmental health disparities and adverse health outcomes indicates a need for further study.

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.

Numerous epidemiological and animal studies have demonstrated that exposure to ambient fine particulate matter (<2.5mum in diameter [PM2.5]) during gestation is associated with adverse obstetric outcomes including preterm birth (PTB). Early delivery has been linked to several lifetime health consequences for offspring, including behavioral and psychological abnormalities and reduced immune and respiratory functions. In a previous study performed in this laboratory, B6C3F1 pregnant mice exposed to concentrated ambient PM (CAPs) by inhalation, demonstrated shortened (by 0.4 d) gestational duration compared to filtered air (FA) controls. The mechanisms underlying the association between PM2.5 and PTB are not currently well understood. Since the placenta provides a crucial link between the intrauterine environment and fetal growth/development, it is a major target of PM and key for studying the effects on birth outcomes. Therefore, in this study, placentae from the previously developed pregnant mouse model (n=6 each from CAPs and FA groups) were subjected to whole transcriptomic profiling by RNAseq. A bioinformatic RNAseq analysis workflow (tximport, Salmon and edgeR /limmavoom) was used to identify differentially expressed genes between treatment groups. The 648 genes from the curated dbPTB (database Preterm Birth) were used for a candidate gene approach and were examined using gene counts obtained from RNAseq. Following PM2.5 exposure, six PTB genes were downregulated in placentae (Ace, Ddah1, Col1a2, Chst15, Akap12, Ephx1) and one was upregulated (Chys3) (p<0.01). Gene Ontology demonstrated that these seven genes are involved in neutrophil-mediated immunity, arterial blood pressure regulation, amino acid binding, cell membrane function, metal ion binding, and aromatic compound catabolism among other functions that could be linked to PTB. Additional computational models, agnostically testing placenta transcriptome-wide differential gene expression, revealed additional genes that were differentially expressed between the two treatment groups. These findings suggest that PM exposure influences the placenta genome thereby mediating PTB. Identification of these differentially expressed genes may contribute to intervention strategies to mitigate these adverse effects

World Trade Center (WTC) responders were exposed to mixture of dust, smoke, chemicals and carcinogens. New York University (NYU) and Mount Sinai have recreated WTC exposure in rodents to observe the resulting systemic and local biological responses. These experiments aid in the interpretation of epidemiological observations and are useful for understanding the carcinogenesis process in the exposed human WTC cohort. Here we describe the implementation of a tissue bank system for the rodents experimentally exposed to WTC dust. NYU samples were experimentally exposed to WTC dust via intratracheal inhalation that mimicked conditions in the immediate aftermath of the disaster. Tissue from Mount Sinai was derived from genetically modified mice exposed to WTC dust via nasal instillation. All processed tissues include annotations of the experimental design, WTC dust concentration/dose, exposure route and duration, genetic background of the rodent, and method of tissue isolation/storage. A biobank of tissue from rodents exposed to WTC dust has been compiled representing an important resource for the scientific community. The biobank remains available as a scientific resource for future research through established mechanisms for samples request and utilization. Studies using the WTC tissue bank would benefit from confirming their findings in corresponding tissues from organs of animals experimentally exposed to WTC dust. Studies on rodent tissues will advance the understanding of the biology of the tumors developed by WTC responders and ultimately impact the modalities of treatment, and the probability of success and survival of WTC cancer patients.

An excess incidence of prostate cancer has been identified among World Trade Center (WTC) responders. In this study, we hypothesized that WTC dust, which contained carcinogens and tumor-promoting agents, could facilitate prostate cancer development by inducing DNA damage, promoting cell proliferation, and causing chronic inflammation. We compared expression of immunologic and inflammatory genes using a NanoString assay on archived prostate tumors from WTC Health Program (WTCHP) patients and non-WTC patients with prostate cancer. Furthermore, to assess immediate and delayed responses of prostate tissue to acute WTC dust exposure via intratracheal inhalation, we performed RNA-seq on the prostate of normal rats that were exposed to moderate to high doses of WTC dust. WTC prostate cancer cases showed significant upregulation of genes involved in DNA damage and G₂-M arrest. Cell-type enrichment analysis showed that Th17 cells, a subset of proinflammatory Th cells, were specifically upregulated in WTC patients. In rats exposed to WTC dust, we observed upregulation of gene transcripts of cell types involved in both adaptive immune response (dendritic cells and B cells) and inflammatory response (Th17 cells) in the prostate. Unexpectedly, genes in the cholesterol biosynthesis pathway were also significantly upregulated 30 days after acute dust exposure. Our results suggest that respiratory exposure to WTC dust can induce inflammatory and immune responses in prostate tissue.Implications: WTC-related prostate cancer displayed a distinct gene expression pattern that could be the result of exposure to specific carcinogens. Our data warrant further epidemiologic and cellular mechanistic studies to better understand the consequences of WTC dust exposure.Visual Overview: http://mcr.aacrjournals.org/content/early/2019/06/18/1541-7786.MCR-19-0115/F1.large.jpg.

Approximately 1 million women smoke during pregnancy despite evidence demonstrating serious juvenile and/or adult diseases being linked to early-life exposure to cigarette smoke. Susceptibility could be determined by factors in previous generations, that is, prenatal or "maternal" exposures to toxins. Prenatal exposure to airborne pollutants such as mainstream cigarette smoke has been shown to induce early-life insults (i.e., gene changes) in Offspring that serve as biomarkers for disease later in life. In this investigation, we have evaluated genome-wide changes in the lungs of mouse Dams and their juvenile Offspring exposed prenatally to mainstream cigarette smoke. An additional lung model was tested alongside the murine model, as a means to find an alternative in vitro, human tissue-based replacement for the use of animals in medical research. Our toxicogenomic and bio-informatic results indicated that in utero exposure altered the genetic patterns of the fetus, which could put them at greater risk for developing a range of chronic illnesses in later life. The genes altered in the in vitro, cell culture model were reflected in the murine model of prenatal exposure to mainstream cigarette smoke. The use of alternative in vitro models derived from human medical waste tissues could be viable options to achieve human endpoint data and conduct research that meets the remits for scientists to undertake the 3Rs practices.

Accumulating evidence indicates the developing central nervous system (CNS) is a target of air pollution toxicity. Epidemiological reports increasingly demonstrate that exposure to the particulate matter (PM) fraction of air pollution during neurodevelopment is associated with an increased risk of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD). These observations are supported by animal studies demonstrating prenatal exposure to concentrated ambient PM induces neuropathologies characteristic of ASD, including ventriculomegaly and aberrant corpus callosum (CC) myelination. Given the role of the CC and cerebellum in ASD etiology, this study tested whether prenatal exposure to concentrated ambient particles (CAPs) produced pathological features in offspring CC and cerebella consistent with ASD. Analysis of cerebellar myelin density revealed male-specific hypermyelination in CAPs-exposed offspring at postnatal days (PNDs) 11-15 without alteration of cerebellar area. Atomic absorption spectroscopy (AAS) revealed elevated iron (Fe) in the cerebellum of CAPs-exposed female offspring at PNDs 11-15, which connects with previously observed elevated Fe in the female CC. The presence of Fe inclusions, along with aluminum (Al) and silicon (Si) inclusions, were confirmed at nanoscale resolution in the CC along with ultrastructural myelin sheath damage. Furthermore, RNAseq and gene ontology (GO) enrichment analyses revealed cerebellar gene expression was significantly affected by sex and prenatal CAPs exposure with significant enrichment in inflammation and transmembrane transport processes that could underlie observed myelin and metal pathologies. Overall, this study highlights the ability of PM exposure to disrupt myelinogenesis and elucidates novel molecular targets of PM-induced developmental neurotoxicity.

Syngeneic murine tumor models have been widely used by researchers to assess changes in tumor susceptibility associated with exposure to toxicants. Two common tumor models used to define host resistance against transplanted tumors in vivo are EL4 mouse lymphoma cells (established from a lymphoma induced in a C57BL/6 mouse by 9,10-dimethyl-1,2-benzanthracene) and B16F10 mouse melanoma cells (derived through variant selection from a B16 melanoma arising spontaneously in C57BL/6 mice). While C57BL/6 mice are commonly used as the syngeneic host for these tumor models, other mouse strains such as B₆C₃F₁ (C57BL/6 × C3H) can also be used. Tumor challenge of the host can be done by subcutaneous (sc) or intravenous (iv) injection, depending upon whether the effects are to be examined on local tumor development or experimental/artificial metastasis. Materials and methodologies for injection of both tumor cell models are described in detail in the subsequent sections.

Xenobiotic exposures affect the maternal and/or in utero environment resulting in impairments in fetal development. During the period of rapid fetal growth, developing cardiovascular systems are especially vulnerable to their environment. Furthermore, fetal exposures can evoke changes in epigenetic signatures that result in permanent modifications in gene expression. This symposium focused on the intersection between maternal and fetal exposure and the developing cardiovascular system. The impact of maternal exposures on prenatal development is of major concern for regulatory agencies given the unique vulnerability of the embryo/fetus to environmental factors, the importance of vascular biology to maternal-fetal interactions, and the adverse consequences of vascular disruption to children's health. Speakers provided data from diverse exposures: nanomaterials, particulate matter or air pollution (PM_2.5), nicotine, and environmental chemicals. The current findings related to susceptible gestational windows for cardiovascular development and epigenetic, transcriptomic, toxicokinetic, and toxicodynamic changes in vascular physiology and cardiac function. In response to these concerns, new concepts in predictive modeling and risk assessment associated with in utero exposures were presented as future avenues of research within developmental toxicology. Finally, current applications using an Adverse Outcome Pathway framework for developmental toxicity were presented to integrate data from in vitro profiling of chemical libraries (e.g. ToxCastâ„¢) with computational models for in silico toxicology. In summary, this symposium addressed the significant threats to cardiovascular health that are associated with fetal/perinatal exposures, and offered new insights into the predictive, mechanistic, and risk assessment strategies in developmental toxicology.