Project description:Atrazine (ATZ) and nonylphenol (NP) are commonly identified contaminants in aquatic habitats; however, relatively few studies have considered the impact of these endocrine disrupters on immune function. This study examined the immunotoxicological effects of ATZ and NP at multiple levels of biological organization. Juvenile rainbow trout (Oncorhynchus mykiss) were exposed to a solvent control (0.00625 % v/v anhydrous ethanol), 59 µg/L ATZ, 555 µg/L ATZ, 2.3 µg/L NP or 18 µg/L NP (measured concentrations) for 4 d. At the end of exposure, fish were assessed for general health indicators (liver somatic index (LSI), spleen somatic index (SSI), hematocrit), biochemical endpoints (plasma cortisol concentrations, lysozyme activity, and protein content), a cellular endpoint (blood leukocyte differential counts), and an integrated immune response at the organism level (host resistance challenge with Listonella anguillarum). Additionally, liver gene expression was assessed using a salmonid microarray (cGRASP, 32K version 1) for fish exposed to the (solvent) control, high ATZ (555 µg/L) and high NP (18 µg/L) treatments. Fish exposed to the high ATZ concentration exhibited elevated plasma cortisol, a decrease in SSI, and decreased lymphocytes and increased monocytes in peripheral blood, with suppression of early immune system processes apparent at the molecular level. In contrast, fish exposed to the high NP concentration showed physiological (e.g. elevated LSI) and gene expression changes (e.g. induction of vitellogenin) consistent with estrogenic effects, as well as decreased lymphocytes in the peripheral blood and more limited alteration in immune system related pathways in the liver transcriptome. Fish exposed to high ATZ or NP concentrations suffered higher mortality than the control group following disease challenge with L. anguillarum. Microarray analysis of the liver transcriptome revealed a total of 211 unique, annotated differentially-regulated genes (DRGs) following high ATZ exposure and 294 DRGs following high NP exposure, with signatures that included alterations to a number of immune-system related processes and pathways. Functional (enrichment) analysis revealed effects on immune system function, metabolism, oxygen homeostasis, cell cycle, DNA damage, and other processes affected by ATZ or NP exposure. Overall this study provides evidence at multiple levels of biological organization that both ATZ and NP are immunotoxic and highlights the potential risk posed by these chemicals to wild fish populations. Total of 24 microarrays. 1 experimental sample and 1 pooled reference sample per microarray. Total of 8 individual samples (replicates) per treatment group. Three (3) treatment groups: control, atrazine (ATZ, 555 ug/L) and nonylphenol (NP, 18 ug/L).

Project description:Atrazine (ATZ) and nonylphenol (NP) are commonly identified contaminants in aquatic habitats; however, relatively few studies have considered the impact of these endocrine disrupters on immune function. This study examined the immunotoxicological effects of ATZ and NP at multiple levels of biological organization. Juvenile rainbow trout (Oncorhynchus mykiss) were exposed to a solvent control (0.00625 % v/v anhydrous ethanol), 59 µg/L ATZ, 555 µg/L ATZ, 2.3 µg/L NP or 18 µg/L NP (measured concentrations) for 4 d. At the end of exposure, fish were assessed for general health indicators (liver somatic index (LSI), spleen somatic index (SSI), hematocrit), biochemical endpoints (plasma cortisol concentrations, lysozyme activity, and protein content), a cellular endpoint (blood leukocyte differential counts), and an integrated immune response at the organism level (host resistance challenge with Listonella anguillarum). Additionally, liver gene expression was assessed using a salmonid microarray (cGRASP, 32K version 1) for fish exposed to the (solvent) control, high ATZ (555 µg/L) and high NP (18 µg/L) treatments. Fish exposed to the high ATZ concentration exhibited elevated plasma cortisol, a decrease in SSI, and decreased lymphocytes and increased monocytes in peripheral blood, with suppression of early immune system processes apparent at the molecular level. In contrast, fish exposed to the high NP concentration showed physiological (e.g. elevated LSI) and gene expression changes (e.g. induction of vitellogenin) consistent with estrogenic effects, as well as decreased lymphocytes in the peripheral blood and more limited alteration in immune system related pathways in the liver transcriptome. Fish exposed to high ATZ or NP concentrations suffered higher mortality than the control group following disease challenge with L. anguillarum. Microarray analysis of the liver transcriptome revealed a total of 211 unique, annotated differentially-regulated genes (DRGs) following high ATZ exposure and 294 DRGs following high NP exposure, with signatures that included alterations to a number of immune-system related processes and pathways. Functional (enrichment) analysis revealed effects on immune system function, metabolism, oxygen homeostasis, cell cycle, DNA damage, and other processes affected by ATZ or NP exposure. Overall this study provides evidence at multiple levels of biological organization that both ATZ and NP are immunotoxic and highlights the potential risk posed by these chemicals to wild fish populations.

Project description:According to the developmental origins of health and disease (DOHaD) hypothesis, exposure to environmental stressors during early development can cause genetic, epigenetic, or functional changes in tissues that increase disease risk later in life. Atrazine (ATZ) is a commonly used pesticide that frequently contaminates rural and urban water sources at levels above the 3 ppb maximum contaminant level set by the US Environmental Protection Agency. Exposure to ATZ is linked to endocrine disruption, cancer, changes in genome methylation, and alterations in neurochemistry and behavior. This study tests the hypothesis that embryonic exposure to ATZ results in sex-specific changes in behavior, the adult brain transcriptome, and adult body and brain pathology, according to the DOHaD hypothesis. Zebrafish (Danio rerio) embryos were exposed to 0, 0.3, 3, or 30 ppb (ppb; µg/L) ATZ during the period from fertilization through 72 hours post fertilization (hpf), and then were rinsed and raised to maturity with no further exposure. At 9 months post fertilization (mpf), a novel tank test, a light-dark box, and an open field test evaluated adult behavior. Transcriptomic analysis investigated ATZ related differences in gene expression and the brain was evaluated histopathologically for morphometric alterations in the area of the dorsal telencephalon, posterior tuberculum, and raphe populations. At 14 mpf, the body length, weight, and brain weight was measured to evaluate effects of ATZ on mature body and brain size. The 9 mpf adult behavioral tests found non-monotonic, sex-specific behavior changes, with male zebrafish having decreased activity and female zebrafish having increased signs of anxiety. Transcriptomic analysis identified sex-specific alterations, with females having altered expression of genes in pathways related to cancer and organismal injury and males having altered gene expression in organismal development and reproductive system development and function pathways. Morphometric analysis identified a decreased number of cells in male raphe populations and adult zebrafish also had non-monotonic, sex-specific alterations in body length, body weight, and brain weight. This results suggests that developmental exposure to ATZ does cause sex-specific alterations in adult neural function.

Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care. Comparison of bleomycin-treated and control rats after 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks; 5 animals per group

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Long-term Atrazine exposure promotes ovarian dysfunction by enhancing the inflammatory microenvironment and inducing fibrosis

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