Meta-Analysis Comparing Nominal and Measured Concentrations of Perfluorooctanoic Acid and Perfluorooctane Sulfonate in Aquatic Toxicity Studies Across Various Experimental Conditions.

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are among the most frequently detected chemicals among the per- and polyfluoroalkyl substances in aquatic environments. Because of their high detection frequency, persistence, and potential toxicity, interest in both PFOA and PFOS has increased in recent years. However, a substantial number of PFOA and PFOS toxicity tests only report nominal, or unmeasured, treatment concentrations, which may complicate the determination of protective values. In addition, previous literature has indicated that differences between nominal and measured concentrations of both PFOA and PFOS could be linked to experimental conditions (e.g., feeding regimes for test organisms, test vessel material [glass or plastic], use of solvent, and the presence of substrate). Therefore, this critical review examined whether nominal and measured concentrations were in close agreement with each other among the current PFOA and PFOS aquatic toxicity literature and if experimental conditions were associated with any observed differences. Nominal and measured concentrations in the current PFOA and PFOS aquatic toxicity literature generally displayed a high degree of linear correlation and relatively low median percent differences. Correlations between measured and nominal concentrations were >0.98 for PFOA and >0.95 for PFOS in freshwater tests across experimental conditions. For saltwater tests, correlations of >0.84 were observed for PFOA and PFOS (separate and combined) across experimental conditions. While measured PFOA and PFOS toxicity tests are generally preferred, the present meta-analysis demonstrated that experimental conditions had little influence on observed discrepancies between nominal and measured concentrations, with the exception of PFOS saltwater tests and PFOA and PFOS freshwater studies that contained substrate. Unmeasured tests with these conditions should be considered carefully based on project needs, with the caveat that the data sets for these two experimental conditions were limited. Environ Toxicol Chem 2023;42:2289-2301. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

Direct and Delayed Mortality of Ceriodaphnia dubia and Rainbow Trout Following Time-Varying Acute Exposures to Zinc.

The potential for delayed mortality following short-term episodic pollution events was evaluated by exposing cladocerans (Ceriodaphnia dubia) and rainbow trout (Oncorhynchus mykiss) to zinc (Zn) in various 1- to 48-h and 1- to 96-h exposures, respectively, followed by transferring the exposed organisms to clean water for up to 47 h for C. dubia and up to 95 h for trout for additional observation. For C. dubia, 1-h exposures of up to 3790 µg Zn/L never resulted in mortality during the actual Zn exposures, but by 48 h, a 1-h exposure to 114 µg/L, a concentration similar to the present US national water quality acute criterion for the test water conditions, ultimately killed 70% of C. dubia. With C. dubia, the speed of action of Zn toxicity was faster for intermediate concentrations than for the highest concentrations tested. For rainbow trout, pronounced delayed mortalities by 96 h only occurred following ≥8-h exposures. For both species, ultimate mortalities from Zn exposures ≤8 h mostly presented as delayed mortalities, whereas for exposures ≥24 h, almost all ultimate mortalities presented during the actual exposure periods. With Zn, risks of delayed mortality following exposures to all concentrations tested were much greater for the more sensitive, small-bodied invertebrate (C. dubia) than for the less sensitive, larger-bodied fish (rainbow trout). These results, along with previous studies, show that delayed mortality is an important consideration in evaluating risks to aquatic organisms from brief, episodic exposures to some substances. Environ Toxicol Chem 2021;40:2484-2498. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Perfluorooctane Sulfonate in US Ambient Surface Waters: A Review of Occurrence in Aquatic Environments and Comparison to Global Concentrations.

Perfluorooctane sulfonate (PFOS) is one of the dominant perfluoroalkyl substances (PFAS) detected in aquatic ecosystems. It has been used in a wide range of industrial and consumer products for decades. The unique properties of PFOS, including its stability and resistance to degradation, have made it highly persistent in the aquatic environment. Because of its persistence, potential toxicity, and occurrence in aquatic ecosystems, interest in PFOS has increased in recent decades. Despite this interest, current information on the environmental distribution of PFOS in ambient surface waters of the United States is fairly limited. This critical review summarizes the currently available literature on PFOS occurrence in surface waters across the United States and highlights existing data gaps. Available data are largely from a handful of study areas with known PFAS manufacturing or industrial uses, with much of the data collected from freshwater systems in eastern states and the upper Midwest. Measured PFOS concentrations in surface waters vary widely, over 8 orders of magnitude, with the highest concentrations occurring downstream from manufacturing and industrial use plants, areas near aqueous film-forming foam-use sites, and sites where PFOS precursors were used in textile treatment. Non-point source-related occurrences are highest near urbanized areas with high population densities. Current data illustrate the occurrence of PFOS in surface waters across multiple US states. Additional data are needed to better understand PFOS occurrence in US aquatic ecosystems, particularly in estuarine and marine systems and where monitoring data are not available (e.g., southwestern, central, and western United States). Additional PFOS occurrence data would provide valuable information on potential spatial and temporal variability in surface waters and possible risks posed to aquatic ecosystems. Environ Toxicol Chem 2021;40:2425-2442. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.

Selection for avian leukosis virus integration sites determines the clonal progression of B-cell lymphomas.

Avian leukosis virus (ALV) is a simple retrovirus that causes a wide range of tumors in chickens, the most common of which are B-cell lymphomas. The viral genome integrates into the host genome and uses its strong promoter and enhancer sequences to alter the expression of nearby genes, frequently inducing tumors. In this study, we compare the preferences for ALV integration sites in cultured cells and in tumors, by analysis of over 87,000 unique integration sites. In tissue culture we observed integration was relatively random with slight preferences for genes, transcription start sites and CpG islands. We also observed a preference for integrations in or near expressed and spliced genes. The integration pattern in cultured cells changed over the course of selection for oncogenic characteristics in tumors. In comparison to tissue culture, ALV integrations are more highly selected for proximity to transcription start sites in tumors. There is also a significant selection of ALV integrations away from CpG islands in the highly clonally expanded cells in tumors. Additionally, we utilized a high throughput method to quantify the magnitude of clonality in different stages of tumorigenesis. An ALV-induced tumor carries between 700 and 3000 unique integrations, with an average of 2.3 to 4 copies of proviral DNA per infected cell. We observed increasing tumor clonality during progression of B-cell lymphomas and identified gene players (especially TERT and MYB) and biological processes involved in tumor progression.

Avian Leukosis Virus Activation of an Antisense RNA Upstream of TERT in B-Cell Lymphomas.

UNLABELLED: Avian leukosis virus (ALV) induces tumors by integrating its proviral DNA into the chicken genome and altering the expression of nearby genes via strong promoter and enhancer elements. Viral integration sites that contribute to oncogenesis are selected in tumor cells. Deep-sequencing analysis of B-cell lymphoma DNA confirmed that the telomerase reverse transcriptase (TERT) gene promoter is a common ALV integration target. Twenty-six unique proviral integration sites were mapped between 46 and 3,552 nucleotides (nt) upstream of the TERT transcription start site, predominantly in the opposite transcriptional orientation to TERT Transcriptome-sequencing (RNA-seq) analysis of normal bursa revealed a transcribed region upstream of TERT in the opposite orientation, suggesting the TERT promoter is bidirectional. This transcript appears to be an uncharacterized antisense RNA. We have previously shown that TERT expression is upregulated in tumors with integrations in the TERT promoter region. We now report that the viral promoter drives the expression of a chimeric transcript containing viral sequences spliced to exons 4 through 7 of this antisense RNA. Clonal expansion of cells with ALV integrations driving overexpression of the TERT antisense RNA suggest it may have a role in tumorigenesis. IMPORTANCE: The data suggest that ALV integrations in the TERT promoter region drive the overexpression of a novel antisense RNA and contribute to the development of lymphomas.

Common Viral Integration Sites Identified in Avian Leukosis Virus-Induced B-Cell Lymphomas.

UNLABELLED: Avian leukosis virus (ALV) induces B-cell lymphoma and other neoplasms in chickens by integrating within or near cancer genes and perturbing their expression. Four genes--MYC, MYB, Mir-155, and TERT--have previously been identified as common integration sites in these virus-induced lymphomas and are thought to play a causal role in tumorigenesis. In this study, we employ high-throughput sequencing to identify additional genes driving tumorigenesis in ALV-induced B-cell lymphomas. In addition to the four genes implicated previously, we identify other genes as common integration sites, including TNFRSF1A, MEF2C, CTDSPL, TAB2, RUNX1, MLL5, CXorf57, and BACH2. We also analyze the genome-wide ALV integration landscape in vivo and find increased frequency of ALV integration near transcriptional start sites and within transcripts. Previous work has shown ALV prefers a weak consensus sequence for integration in cultured human cells. We confirm this consensus sequence for ALV integration in vivo in the chicken genome. IMPORTANCE: Avian leukosis virus induces B-cell lymphomas in chickens. Earlier studies showed that ALV can induce tumors through insertional mutagenesis, and several genes have been implicated in the development of these tumors. In this study, we use high-throughput sequencing to reveal the genome-wide ALV integration landscape in ALV-induced B-cell lymphomas. We find elevated levels of ALV integration near transcription start sites and use common integration site analysis to greatly expand the number of genes implicated in the development of these tumors. Interestingly, we identify several genes targeted by viral insertions that have not been previously shown to be involved in cancer.

Complete genome sequence of an american avian leukosis virus subgroup j isolate that causes hemangiomas and myeloid leukosis.

We report the complete genome sequence of avian leukosis virus subgroup J (ALV-J) isolate PDRC-59831, which causes myeloid leukosis and hemangiomas in chickens. This is an American ALV-J isolate, which was found in a 38-week-old broiler breeder chicken on a farm in Georgia in 2007.

The MET gene is a common integration target in avian leukosis virus subgroup J-induced chicken hemangiomas.

UNLABELLED: Avian leukosis virus subgroup J (ALV-J) is a simple retrovirus that can cause hemangiomas and myeloid tumors in chickens and is currently a major economic problem in Asia. Here we characterize ALV-J strain PDRC-59831, a newly studied U.S. isolate of ALV-J. Five-day-old chicken embryos were infected with this virus, and the chickens developed myeloid leukosis and hemangiomas within 2 months after hatching. To investigate the mechanism of pathogenesis, we employed high-throughput sequencing to analyze proviral integration sites in these tumors. We found expanded clones with integrations in the MET gene in two of the five hemangiomas studied. This integration locus was not seen in previous work characterizing ALV-J-induced myeloid leukosis. MET is a known proto-oncogene that acts through a diverse set of signaling pathways and is involved in many neoplasms. We show that tumors harboring MET integrations exhibit strong overexpression of MET mRNA. IMPORTANCE: These data suggest that ALV-J induces oncogenesis by insertional mutagenesis, and integrations in the MET oncogene can drive the overexpression of MET and contribute to the development of hemangiomas.

Avian retroviral replication.

Avian retroviruses were originally identified as cancer-inducting filterable agents in chicken neoplasms at the beginning of the 20th century. Since their discovery, the study of these simple retroviruses has contributed greatly to our understanding of viral replication and cancer. Avian retroviruses continue to evolve and have great economic importance in the poultry industry worldwide. The aim of this review is to provide a broad overview of the genome, pathology, and replication of avian retroviruses. Notable gaps in our current knowledge are highlighted, and areas where avian retroviruses differ from other retroviruses are emphasized.