Effects of chronic dietary exposure to environmentally relevant concentrations to 2,3,7,8-tetrachlorodibenzo-p-dioxin on survival, growth, reproduction and biochemical responses of female rainbow trout (Oncorhynchus mykiss

Abstract Adult female rainbow trout were exposed to dietary 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at concentrations of 1.8, 18 and 90 ng TCDD/kg (ww) food for up to 300 day. At the end of the exposure fish were spawned and the reproductive outcomes were assessed. TCDD was accumulated into tissues and eggs in a dose-dependent manner with steady state being achieved after 50-100 day of exposure. Biochemical and hematological parameters were monitored at 50, 100, 150, and 200 day after the beginning of exposure. The survival of adult female trout was reduced in a dose-dependent manner by exposure to TCDD in the diet. Fish fed 1.8 ng TCDD/kg, moist weight of diet, showed significantly reduced survival compared with those fed the control diet. TCDD also affected survival of fry from females fed 1.8 ng TCDD/kg. Observed adverse effects in adult fish were as sensitive as early life-stage endpoints. Liver EROD activity was only moderately increased in all exposure groups after 250 + day of exposure. Low rates of edema and deformities were observed in fry from all treatment groups including controls. This study has demonstrated adverse effects of TCDD to both adults and fry at concentrations comparable to current environmental concentrations. This suggests that direct adult toxicity as well as reproductive endpoints need to be incorporated in the current risk assessment paradigm for these compounds

Environmental Toxicology RISK ASSESSMENT OF GREAT HORNED OWLS (BUBO VIRGINIANUS) EXPOSED TO POLYCHLORINATED BIPHENYLS AND DDT ALONG THE KALAMAZOO RIVER, MICHIGAN, USA

Abstract-The great horned owl (GHO; Bubo virginianus) was used in a multiple lines of evidence study of polychlorinated biphenyls (PCBs) and p,pЈ-dichlorodiphenyltrichloroethane (DDT) exposures at the Kalamazoo River Superfund Site (KRSS), Kalamazoo, Michigan, USA. The study examined risks from total PCBs, including 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQ World Health Organization [WHO]-Avian Toxicity Equivalency Factor [TEF] ), and total DDTs (sum of DDT, dichlorodiphenyldichloroethylene [DDE], and dichlorodiphenyldichloroethane [DDD]; ⌺DDT) by measuring concentrations in eggs and nestling blood plasma in two regions of the KRSS (upper, lower) and an upstream reference area (RA). An ecological risk assessment compared concentrations of the contaminants of concern (COCs) in eggs or plasma to toxicity reference values. Productivity and relative abundance measures for KRSS GHOs were compared with other GHO populations. Egg shell thickness was measured to assess effects of p,pЈ-DDE. The concentrations of PCBs in eggs were as great as 4.7 ϫ 10 2 and 4.0 ϫ 10 4 ng PCB/g, wet weight at the RA and combined KRSS sites, respectively. Egg TEQ WHO-Avian calculated from aryl hydrocarbon receptor-active PCB congeners and WHO TEFs ranged to 8.0 and 1.9 ϫ 10 2 pg TEQ WHO-Avian /g, (wet wt) at the RA and combined KRSS, respectively. Egg ⌺DDT concentrations were as great as 4.2 ϫ 10 2 and 5.0 ϫ 10 3 ng ⌺DDT/g (wet wt) at the RA and combined KRSS, respectively. Hazard quotients (HQs) for the upper 95% confidence interval (UCI) (geometric mean) and least observable adverse effect concentration (LOAEC) for COCs in eggs were Յ1.0 for all sites. Hazard quotient values based on the no observable adverse effect concentration (NOAEC) 95% UCI in eggs were Յ1.0, except at the LKRSS (PCB HQ ϭ 3.1; TEQ WHO-Avian HQ ϭ 1.3). Productivity and relative abundance measures indicated no population level effects in the UKRSS

Environmental Toxicology RISK ASSESSMENT OF GREAT HORNED OWLS (BUBO VIRGINIANUS) EXPOSED TO POLYCHLORINATED BIPHENYLS AND DDT ALONG THE KALAMAZOO RIVER, MICHIGAN, USA

Abstract-The great horned owl (GHO; Bubo virginianus) was used in a multiple lines of evidence study of polychlorinated biphenyls (PCBs) and p,pЈ-dichlorodiphenyltrichloroethane (DDT) exposures at the Kalamazoo River Superfund Site (KRSS), Kalamazoo, Michigan, USA. The study examined risks from total PCBs, including 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQ World Health Organization [WHO]-Avian Toxicity Equivalency Factor [TEF] ), and total DDTs (sum of DDT, dichlorodiphenyldichloroethylene [DDE], and dichlorodiphenyldichloroethane [DDD]; ⌺DDT) by measuring concentrations in eggs and nestling blood plasma in two regions of the KRSS (upper, lower) and an upstream reference area (RA). An ecological risk assessment compared concentrations of the contaminants of concern (COCs) in eggs or plasma to toxicity reference values. Productivity and relative abundance measures for KRSS GHOs were compared with other GHO populations. Egg shell thickness was measured to assess effects of p,pЈ-DDE. The concentrations of PCBs in eggs were as great as 4.7 ϫ 10 2 and 4.0 ϫ 10 4 ng PCB/g, wet weight at the RA and combined KRSS sites, respectively. Egg TEQ WHO-Avian calculated from aryl hydrocarbon receptor-active PCB congeners and WHO TEFs ranged to 8.0 and 1.9 ϫ 10 2 pg TEQ WHO-Avian /g, (wet wt) at the RA and combined KRSS, respectively. Egg ⌺DDT concentrations were as great as 4.2 ϫ 10 2 and 5.0 ϫ 10 3 ng ⌺DDT/g (wet wt) at the RA and combined KRSS, respectively. Hazard quotients (HQs) for the upper 95% confidence interval (UCI) (geometric mean) and least observable adverse effect concentration (LOAEC) for COCs in eggs were Յ1.0 for all sites. Hazard quotient values based on the no observable adverse effect concentration (NOAEC) 95% UCI in eggs were Յ1.0, except at the LKRSS (PCB HQ ϭ 3.1; TEQ WHO-Avian HQ ϭ 1.3). Productivity and relative abundance measures indicated no population level effects in the UKRSS

Multiple Lines of Evidence Risk Assessment of Terrestrial Passerines Exposed to PCDFs and PCDDs in the Tittabawassee River Floodplain, Midland, Michigan, USA

A site-specific multiple lines of evidence risk assessment was conducted for house wrens (Troglodytes aedon) and eastern bluebirds (Sialia sialis) along the Tittabawassee River downstream of Midland, Michigan, where concentrations of polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-p-dioxins (PCDDs) in flood-plain soils and sediments are greater compared to upstream areas and some of the greatest anywhere in the world. Lines of evidence supporting the population-level assessment endpoints included site-specific dietary- and tissue-based exposure assessments and population productivity measurements during breeding seasons 2005–2007. While a hazard assessment based on site-specific diets suggested that populations residing in the downstream floodplain had the potential to be affected, concentrations in eggs compared to appropriate toxicity reference values (TRVs) did not predict a potential for population-level effects. There were no significant effects on reproductive success of either species. The most probable cause of the apparent difference between the dietary- and tissue-based exposure assessments was that the dietary-based TRVs were overly conservative based on intraperitoneal injections in the ring-necked pheasant. Agreement between the risk assessment based on concentrations of PCDFs and PCDDs in eggs and reproductive performance in both species supports the conclusion of a small potential for population-level effects at this site

Hepatic P450 Enzyme Activity, Tissue Morphology and Histology of Mink (Mustela vison) Exposed to Polychlorinated Dibenzofurans

Dose- and time-dependent effects of environmentally relevant concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQ) of 2,3,7,8-tetrachlorodibenzofuran (TCDF), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or a mixture of these two congeners on hepatic P450 enzyme activity and tissue morphology, including jaw histology, of adult ranch mink were determined under controlled conditions. Adult female ranch mink were fed either TCDF (0.98, 3.8, or 20 ng TEQTCDF/kg bw/day) or PeCDF (0.62, 2.2, or 9.5 ng TEQPeCDF/kg bw/day), or a mixture of TCDF and PeCDF (4.1 ng TEQTCDF/kg bw/day and 2.8 ng TEQPeCDF/kg bw/day, respectively) for 180 days. Doses used in this study were approximately eight times greater than those reported in a parallel field study. Activities of the cytochrome P450 1A enzymes, ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-deethylase (MROD) were significantly greater in livers of mink exposed to TCDF, PeCDF, and a mixture of the two congeners; however, there were no significant histological or morphological effects observed. It was determined that EROD and MROD activity can be used as sensitive biomarkers of exposure to PeCDF and TCDF in adult female mink; however, under the conditions of this study, the response of EROD/MROD induction occurred at doses that were less than those required to cause histological or morphological changes

Genetically Encoded Synthetic Polypeptides as Innovative Cancer Therapeutics

Ligands based on bicyclic peptides can combine favourable properties of antibodies (good binding affinity and target specificity) and small molecule ligands (stability, access to chemical synthesis, diffusion properties) and might be suitable molecular structures for the development of therapeutics1. By using a combinatorial methodology based on phage display and a chemical cyclisation reaction2, we isolated a potent (Ki = 53 nM) and selective inhibitor of human urokinase-type plasminogen activator (uPA), a trypsin-like serine protease that participates in the turnover of extracellular matrix (ECM) proteins and is implicated in tumor growth and invasion3. X-ray structure determination of the bicyclic peptide bound to uPA revealed that both peptide loops engage the target to form a large interaction surface of 701 Å2 with multiple hydrogen bonds and complementary charge interactions, explaining the high affinity and specificity of the inhibitor. The interface resembles that between two proteins and suggests that these constrained peptides have the potential to act as small protein mimics. Moreover, further study revealed that the in vitro-evolved bicyclic peptide are stable in vivo and remain active for several days overcoming a limitation faced by many in vitro-evolved peptide leads and promises to be suitable for the generation of long-acting peptide therapeutics4,5. Its therapeutic effect is currently being tested in vivo

Binding of perfluorinated fatty acids to serum proteins

Abstract—Perfluorooctane sulfonic acid (PFOS) accumulates in the liver and blood of exposed organisms. The potential for these surfactant molecules to interfere with hormone/protein interactions in blood is of concern given the importance of these interactions. The PFOS binding to serum proteins was investigated by assessing its ability to displace a variety of steroid hormones from specific binding proteins in the serum of birds and fishes. Perfluorooctane sulfonic acid had only a weak ability to displace estrogen or testosterone from carp serum steroid binding proteins. Displacement of cortisone in avian sera occurred at relatively low PFOS concentrations. Corticosterone displacement potency increased with chain length, and sulfonic acids were more potent than carboxylic acids. The PFOS concentrations estimated to cause these effects were 320 mM or greater, equivalent to serum concentrations greater than 160 mg/L. Using mass spectrometry and direct in vitro binding assays, PFOS was demonstrated to bind strongly to bovine serum albumin (BSA) in a 1:1 stoichiometric ratio. It appears that PFOS in serum is in general bound to albumins. Concentrations of PFOS required to saturate albumin would be in excess of 50 to 100 mg/L. Based on current environmental concentrations, it is unlikely that PFOS would cause displacement of hormones from serum proteins in wildlife. Keywords—Perfluorooctane sulfonic acid Hormones Serum protein Fish Bird