Papers by Elaine Faustman
Toxicological Sciences, 2010
Environmental and occupational exposures to heavy metals such as methylmercury (MeHg) and cadmium... more Environmental and occupational exposures to heavy metals such as methylmercury (MeHg) and cadmium (Cd) pose significant health risks to humans, including neurotoxicity. The underlying mechanisms of their toxicity, however, remain to be fully characterized. Our previous studies with Cd and MeHg have demonstrated that the perturbation of the ubiquitin-proteasome system (UPS) was associated with metal-induced cytotoxicity and apoptosis. We conducted a microarray-based gene expression analysis to compare metal-altered gene expression patterns with a classical proteasome inhibitor, MG132 (0.5mM), to determine whether the disruption of the UPS is a critical mechanism of metal-induced toxicity. We treated mouse embryonic fibroblast cells at doses of MeHg (2.5mM) and Cd (5.0mM) for 24 h. The doses selected were based on the neutral red-based cell viability assay where initial statistically significant decreases in variability were detected. Following normalization of the array data, we employed multilevel analysis tools to explore the data, including group comparisons, cluster analysis, gene annotations analysis (gene ontology analysis), and pathway analysis using GenMAPP and Ingenuity Pathway Analysis (IPA). Using these integrated approaches, we identified significant gene expression changes across treatments within the UPS (Uchl1 and Ube2c), antioxidant and phase II enzymes (Gsta2, Gsta4, and Noq1), and genes involved in cell cycle regulation pathways (ccnb1, cdc2a, and cdc25c). Furthermore, pathway analysis revealed significant alterations in genes implicated in Parkinson's disease pathogenesis following metal exposure. This study suggests that these pathways play a critical role in the development of adverse effects associated with metal exposures.
Toxicology and Applied Pharmacology, 2016
MicroRNAs (miRNAs) are post-transcriptional regulators that silence messenger RNAs. Because miRNA... more MicroRNAs (miRNAs) are post-transcriptional regulators that silence messenger RNAs. Because miRNAs are stable at room temperature and long-lived, they have been proposed as molecular biomarkers to monitor disease and exposure status. While urinary miRNAs have been used clinically as potential diagnostic markers for kidney and bladder cancers and other diseases, their utility in non-clinical settings has yet to be fully developed. Our goal was to investigate the potential of urinary miRNAs to act as biomarkers of pesticide exposure and early biological response by identifying the miRNAs present in urine from 27 parent/child, farmworker/nonfarmworker pairs (16FW/11NFW) collected during two agricultural seasons (thinning and postharvest) and characterizing the between-and within-individual variability of these miRNA epigenetic regulators. MiRNAs were isolated from archived urine samples and identified using PCR arrays. Comparisons were made between age, households, season, and occupation. Of 384 miRNAs investigated, 297 (77%) were detectable in at least one sample. Seven miRNAs were detected in at least 50% of the samples, and one miRNA was present in 96% of the samples. Principal components and hierarchical clustering analyses indicate significant differences in miRNA profiles between farmworker and non-farmworker adults as well as between seasons. Six miRNAs were observed to be positively associated with farmworkers status during the postharvest season. Expression of five of these miRNA trended towards a positive dose response relationship with organophosphate pesticide metabolites in farmworkers. These results suggest that miRNAs may be novel biomarkers of pesticide exposure and early biological response.
Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals, Jan 19, 2017
Organophosphorus insecticides (OPs) have been used to control agricultural pests found in Washing... more Organophosphorus insecticides (OPs) have been used to control agricultural pests found in Washington state. Farmworkers (FW) have higher exposure to OP pesticides than non-farmworkers (NFW), and FW children may in turn have higher exposure than NFW children. To examine the association between the concentration in house dust of five OPs used commonly in pome fruit orchards and the concentration in urine of dialkylphosphate metabolites (DAP), in a cohort of Hispanic FW and NFW and their children. Parents and children participated in three data collection periods over the course of one year. Urine samples were evaluated for the DAPs characteristic of OP exposure, and dust from homes and vehicles was evaluated for intact OP residues. Geometric mean (GM) concentrations of OPs in house and vehicle dust were higher in FW households than NFW households in all agricultural seasons. GM concentration of urinary DAPs was higher for children in FW households than NFW households. Regression analy...
The overall goal of this project is to evaluate risk assessment methods traditionally used for no... more The overall goal of this project is to evaluate risk assessment methods traditionally used for noncancer health risks and to compare them with new approaches. Initially this report gives a brief economic rationale for the impact of prevention of noncancer health effects. This is shown using figures for years of potential life lost which reveal that noncancer health effects, such as birth defects, are on the same national economic magnitude as cancer and heart disease. Traditional approaches for assessing these noncancer risks are discussed. These methods include identification of no observed adverse effect levels (NOAELs). Reference dose (RfD) calculation or setting of acceptable daily intake (ADI) values is achieved by dividing the NOAEL values by uncertainty and/or modifying factors. These factors represent a default approach to response). This illustrates an important advantage of BMD approaches in that a regulatory limit can be consistently set at a given response level rather than being dictated by study design. The benchmark dose method rewards adequately designed experiments by setting higher BMD values, which is in direct contrast to the NOAEL approach. Using curve-fitting procedures, the calculation of RfD values is no longer constrained to be one of the experimental doses tested. BMD methodology will allow for easy transition to truly biologically based dose response modeling when such models are developed. This review discusses several new areas of research on this topic. In summary, both research and philosophical advantages of BMD approaches are given in this report.
Toxicological sciences : an official journal of the Society of Toxicology, 2005
Investigations into the potential mechanisms for ethanol-induced developmental toxicity have been... more Investigations into the potential mechanisms for ethanol-induced developmental toxicity have been ongoing for over 30 years since Fetal Alcohol Syndrome (FAS) was first described. Neurodevelopmental endpoints are particularly sensitive to in utero exposure to alcohol as suggested by the more prevalent alcohol-related neurodevelopmental disorder (ARND). The inhibition of proliferation during neurogenesis and the induction of apoptosis during the period of synaptogenesis have been identified as potentially important mechanisms for ARND. However, it is unclear how these two mechanisms quantitatively relate to the dose and timing of exposure. We have extended our model of neocortical neurogenesis to evaluate apoptosis during synaptogenesis. This model construct allows quantitative evaluation of the relative impacts on neuronal proliferation versus apoptosis during neocortical development. Ethanol-induced lengthening of the cell cycle of neural progenitor cells during rat neocortical neu...
Fundamental and applied toxicology : official journal of the Society of Toxicology, 1995
Recently, most attention on the application of benchmark dose (BMD) techniques to toxicology data... more Recently, most attention on the application of benchmark dose (BMD) techniques to toxicology data has focused on quantal measures of response. Before the advantages of the BMD approach can be exploited in the risk assessment process, it is important that continuous measures of response also be modeled appropriately. In this study, we examined a variety of approaches to estimating BMDs for a change in fetal weight following chemical exposure from a total of 85 developmental toxicity experiments. We modeled the change in the mean fetal weight of a litter in response to treatment using a continuous power model, as well as reductions in the weight of individual fetuses within litters (defined as falling below a preset level) using a log-logistic model which incorporates litter size as a covariable and considers intralitter correlations. For the litter-based approach, several methods of defining a benchmark effect (BME) were considered, including a percentage change in mean litter weight...
This review presents a brief overview of Internet resources that provides information on developm... more This review presents a brief overview of Internet resources that provides information on developmental toxicity. The advantages and limitations of these resources for evaluating human risk and where each one is useful for informing various stages of the risk assessment process (i.e. hazard characterization, dose-response assessment, exposure assessment and risk characterization) are reviewed. How these Internet resources can be utilized to obtain information on and evaluate the developmental risk associated with exposures during pregnancy will be illustrated using toluene. Translating information derived from laboratory and human population studies into clinical management prescriptions for individual patients is difficult. With the increasing availability of Internet resources that provide information relevant for developmental risk assessments, health care professionals will be better equipped to make more accurate estimations of potential risk for their patients.
Toxicology and Applied Pharmacology, 2008
Arsenic (As) is a well-known environmental toxicant and carcinogen as well as an effective chemot... more Arsenic (As) is a well-known environmental toxicant and carcinogen as well as an effective chemotherapeutic agent. The underlying mechanism of this dual capability, however, is not fully understood. Tumor suppressor gene p53, a pivotal cell cycle checkpoint signaling protein, has been hypothesized to play a possible role in mediating As-induced toxicity and therapeutic efficiency. In this study, we found that arsenite (As 3+ ) induced apoptosis and cell cycle arrest in a dose-dependent manner in both p53+/+ and p53−/− mouse embryonic fibroblasts (MEFs). There was, however, a distinction between genotypes in the apoptotic response, with a more prominent induction of caspase-3 in the p53−/− cells than in the p53+/+ cells. To examine this difference further, a systemsbased genomic analysis was conducted comparing the critical molecular mechanisms between the p53 genotypes in response to As 3+ . A significant alteration in the Nrf2-mediated oxidative stress response pathway were found in both genotypes. In p53+/+ MEFs, As 3+ induced p53-dependent gene expression alterations in DNA damage and cell cycle regulation genes. However, in the p53−/− MEFs, As 3+ induced a significant up-regulation of pro-apoptotic genes (Noxa) and down-regulation of genes in immune modulation. Our findings demonstrate that As-induced cell death occurs through a p53-independent pathway in p53 deficient cells while apoptosis induction occurs through p53dependent pathway in normal tissue. This difference in the mechanism of apoptotic responses between the genotypes provides important information regarding the apparent dichotomy of arsenic's dual mechanisms, and potentially leads to further advancement of its utility as a chemotherapeutic agent.
Neurotoxicology and Teratology, 2010
Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. A... more Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have not been adequately addressed. This research investigated doseresponse relationships of TH insufficiency on TH action in developing brain. Three methods to perturb the thyroid axis were employed: propylthiouracil (PTU), dietary iodine deficiency, and perchlorate. PTU inhibits TH synthesis; iodine is an essential element for TH synthesis; and perchlorate is an environmental contaminant that blocks iodine uptake. These treatments were delivered via drinking water or food, producing graded levels of TH reduction during gestation and lactation. TH-responsive genes were examined in cortex of offspring on PN14. A set of 8 genes that were significantly altered in a gene array analysis by PTU was selected based on the magnitude of change, significance to brain development, and link to thyroid function. Gene-expression was determined using qRT-PCR and used as an estimate of TH action, i.e., an indication of adequate levels of TH in critical target tissues. Dose-dependent reductions in expression of a number of genes were observed that were similar across different modes of thyroid-axis perturbation. Significant reductions were also observed at doses that produced mild reductions in circulating TH in dams or offspring. These findings suggest that autoregulatory mechanisms of the thyroid axis may be insufficient to maintain required tissue levels of TH in the developing brain. (Does not necessarily reflect EPA policy.) Pregnant C57Bl/6J mice were injected subcutaneously daily from GD6 to GD17 with chlorpyrifos (dissolved in DMSO) at 0, 2, 4, or 12 mg/kg/day. Control mice received DMSO alone. Experiments were conducted in three cohorts as part of a larger study that examined other endpoints of toxicity (global gene expression and acetylcholinesterase activity in dams and fetuses). On postnatal day 4 after parturition, litters were culled to six mice (3 males and 3 females). One male and one female from each litter were assigned randomly to "neurobehavioral assessment group A" and one male and one female were assigned to "neurobehavioral assessment group B", with the remaining two mice used for measurement of brain acetylcholinesterase activity. At weaning, mice were transferred to the neurobehavioral testing facility and housed two per cage for the duration of testing. No overt signs of cholinergic toxicity, such as tremors or difficulty breathing, were observed in pregnant females or offspring. Postnatal weight gain was significantly reduced in chlorpyrifosexposed offspring. Chlorpyrifos exposure delayed reflex righting but accelerated negative geotaxis behavior. A gender specific effect of chlorpyrifos exposure was observed on cued fear conditioning. Male offspring exposed to chlorpyrifos exhibited lower response rates (% freezing) to the cue (tone) than controls. Chlorpyrifos exposure affected Morris maze acquisition, retention and reversal. Most effects were observed at the 12 mg/kg/day dosage. The results indicate that chlorpyrifos affects a wide range of developmental processes. (Supported by CHC grants 5-P01-ES009601 NIEHS/NIH and RD-83170901-0 EPA and CEEH grant 5 P30 ES07033 NIEHS.)
Environmental Health Perspectives, 2006
Organophosphate (OP) pesticides are commonly used in the United States, and farmworkers are at ri... more Organophosphate (OP) pesticides are commonly used in the United States, and farmworkers are at risk for chronic exposure. Using a sample of 218 farmworkers in 24 communities and labor camps in eastern Washington State, we examined the association between agricultural crop and OP pesti- cide metabolite concentrations in urine samples of adult farmworkers and their children and OP pesticide residues
Toxicological Sciences, 2006
Arsenite (As3+) exposure during development has been associated with neural tube defects and othe... more Arsenite (As3+) exposure during development has been associated with neural tube defects and other structural malformations, and with behavioral alterations including altered locomotor activity and operant learning. The molecular mechanisms underlying these effects are uncertain. Because arsenic can cross the placenta and accumulate in the developing neuroepithelium, we examined cell cycling effects of sodium arsenite (As3+ 0, 0.5, 1, 2, and 4 microM) on embryonic primary rat midbrain (gestational day [GD] 12) neuroepithelial cells over 48 h. There was a concentration- and time-dependent As3+-induced reduction in cell viability assessed by neutral red dye uptake assay but minimal apoptosis at concentrations below 4 microM. Morphologically, apoptosis was not apparent until 4 microM at 24 h, which was demonstrated by a marginal but statistically significant increase in cleaved caspase-3/7 activity. Cell cycling effects over several rounds of replication were determined by continuous 5-bromo-2'-deoxyuridine (BrdU) labeling and bivariate flow cytometric Hoechst-Propidium Iodide analysis. We observed a time- and concentration-dependent inhibition of cell cycle progression as early as 12 h after exposure (> or =0.5 microM). In addition, data demonstrated a concentration-dependent increase in cytostasis within all cell cycle phases, a decreased proportion of cells able to reach the second cell cycle, and a reduced cell cycle entry from gap 1 phase (G1). The proportion of affected cells and the severity of the cell cycle perturbation, which ranged from a decreased transition probability to complete cytostasis in all cell cycle phases, were also found to be concentration-dependent. Together, these data support a role for perturbed cell cycle progression in As3+ mediated neurodevelopmental toxicity.
Developmental Brain Research, 2003
We employed 5-bromo-2′-deoxyuridine (BrdU) labeling to identify in vivo changes in the cell cycle... more We employed 5-bromo-2′-deoxyuridine (BrdU) labeling to identify in vivo changes in the cell cycle patterns of the rat midbrain during the major period of midbrain organogenesis, gestational days (gd) 11 to 16. We also used quantitative stereology to determine changes in absolute cell numbers during these gestational time points. Between gd 12 and 16, the length of S-phase did not
Environmental Research, 2000
Regulatory guidelines regarding methylmercury exposure depend on dose–response models relating ob... more Regulatory guidelines regarding methylmercury exposure depend on dose–response models relating observed mercury concentrations in maternal blood, cord blood, and maternal hair to developmental neurobehavioral endpoints. Generalized estimates of the maternal blood-to-hair, blood-to-intake, or hair-to-intake ratios are necessary for linking exposure to biomarker-based dose–response models. Most assessments have used point estimates for these ratios; however, significant inter-individual and interstudy variability has
Journal of Toxicology and Environmental Health, 1992
The objective of this in vitro study was to examine the response of mixed cultures of Sertoli and... more The objective of this in vitro study was to examine the response of mixed cultures of Sertoli and germ cells to treatment with thallium (Tl) at the range of concentrations that, in previous studies, was shown in vivo to affect reproduction. Cultures were prepared from the testis of Sprague-Dawley rats. Cultures containing approximately 3.75 x 10(6) cells/ml were treated with Tl concentrations corresponding to 35, 7, and 1.4 micrograms Tl/g testis, estimated from protein content of cultures. Observations at 24, 48, and 72 h after treatment showed a significant release of germ cells into the culture medium that was both concentration and time dependent. Cultures treated with 35 micrograms Tl/g testis showed a threefold increase in germ-cell detachment compared with controls after only 24 h of exposure. As the treatment time increased to 48 h of exposure, even cultures exposed at the lowest Tl concentration (1.4 micrograms Tl/g testis) showed significant loss of germ cells. After 48 h, cultures exposed to 7 micrograms Tl/g testis exhibited a 2.5-fold increase in germ-cell detachment, and those exposed to 35 micrograms Tl/g testis exhibited a 10-fold increase over controls. Morphological investigations of cell cultures showed evident loss of germ cells with significant reduction in prepachytene and pachytene spermatocytes and changes in the shape of Sertoli cells. These results are in agreement with in vivo studies, in which thallium treatment at comparable exposure levels manifested its earliest toxic testicular effects in Sertoli and germ cells. They also demonstrate the usefulness of this in vitro culture technique to assess toxic testicular damage rapidly.
,RASS Best Abstract Awards ,RASS Best Manuscript Awards ,Remarks by Incoming President ,Point... more ,RASS Best Abstract Awards ,RASS Best Manuscript Awards ,Remarks by Incoming President ,Point / Counterpoint: “Risk Assessment in the 21st Century: Is Everything Linear?”
Teratology, 2002
The period of neurogenesis represents a window of susceptibility for in utero methylmercury (MeHg... more The period of neurogenesis represents a window of susceptibility for in utero methylmercury (MeHg) exposure. This study examined the toxicokinetics of potentially neurotoxic doses of MeHg during neurogenesis in the developing rat to provide additional information in the areas of mercury speciation and inter-study variability. Pregnant Sprague-Dawley rats were dosed s.c. with 5-22 mg/kg MeHg on Day 11 of gestation to target rapidly dividing cells of the developing midbrain. Maternal liver, kidney, skin, blood, placenta, and the embryonic body and brain were evaluated for total and inorganic mercury content at 24, 48, and 72 hr after dosing. Tissue Hg partitioning ratios derived from our data were then compared to those derived from previous studies. Mercury was present in all tissues examined by 24 hr after dosing, and levels remained relatively stable over the subsequent 2 days in most tissues. The exceptions were the maternal blood and kidney, in which total mercury decreased significantly over the three days after dosing. Inorganic mercury concentrations were similarly stable over time. At maternal MeHg doses above 12 mg/kg, non-linearities were observed in mercury accumulation in the embryo, placenta and maternal liver. The mercury tissue partitioning coefficients ranged from 0.09 for maternal blood:embryo to 1.97 for maternal blood:kidney. Our observations at the 5 mg/kg dose were consistent with those of previous studies that involved evaluations at slightly later gestational times. The estimates of tissue partitioning coefficients we derived using multiple studies provide valuable insight into the effects of inter-study variability.
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Papers by Elaine Faustman