Synergistic Embryotoxicity of Polycyclic Aromatic Hydrocarbon Aryl Hydrocarbon Receptor Agonists with Cytochrome P4501A Inhibitors in Fundulus heteroclitus

Widespread contamination of aquatic systems with polycyclic aromatic hydrocarbons (PAHs) has led to concern about effects of PAHs on aquatic life. Some PAHs have been shown to cause deformities in early life stages of fish that resemble those elicited by planar halogenated aromatic hydrocarbons (pHAHs) that are agonists for the aryl hydrocarbon receptor (AHR). Previous studies have suggested that activity of cytochrome P4501A, a member of the AHR gene battery, is important to the toxicity of pHAHs, and inhibition of CYP1A can reduce the early-life-stage toxicity of pHAHs. In light of the effects of CYP1A inhibition on pHAH-derived toxicity, we explored the impact of both model and environmentally relevant CYP1A inhibitors on PAH-derived embryotoxicity. We exposed Fundulus heteroclitus embryos to two PAH-type AHR agonists, β-naphthoflavone and benzo(a)pyrene, and one pHAH-type AHR agonist, 3,3′,4,4′,5-pentachlorobiphenyl (PCB-126), alone and in combination with several CYP1A inhibitors. In agreement with previous studies, coexposure of embryos to PCB-126 with the AHR antagonist and CYP1A inhibitor α-naphthoflavone decreased frequency and severity of deformities compared with embryos exposed to PCB-126 alone. In contrast, embryos coexposed to the PAHs with each of the CYP1A inhibitors tested were deformed with increased severity and frequency compared with embryos dosed with PAH alone. The mechanism by which inhibition of CYP1A increased embryotoxicity of the PAHs tested is not understood, but these results may be helpful in elucidating mechanisms by which PAHs are embryotoxic. Additionally, these results call into question additive models of PAH embryotoxicity for environmental PAH mixtures that contain both AHR agonists and CYP1A inhibitors

Inhibition of an Alzheimer’s disease–associated form of necroptosis rescues neuronal death in mouse models

Necroptosis is a regulated form of cell death that has been observed in Alzheimer's disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)-Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as "GVD-necroptosis" may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD

Hexabromocyclododecanes (HBCDs) in the environment and humans: A review

Hexabromocyclododecanes (HBCDs) are brominated aliphatic cyclic hydrocarbons used as flame retardants in thermal insulation building materials, upholstery textiles, and electronics. As a result of their widespread use and their physical and chemical properties, HBCDs are now ubiquitous contaminants in the environment and humans. This review summarizes HBCD concentrations in several environmental compartments and analyzes these data in terms of point sources versus diffuse sources, biomagnification potential, stereoisomer profiles, time trends, and global distribution. Generally, higher concentrations were measured in samples (air, sediment, and fish) collected near point sources (plants producing or processing HBCDs), while lower concentrations were recorded in samples from locations with no obvious sources of HBCDs. High concentrations were measured in top predators, such as marine mammals and birds of prey (up to 9600 and 19 200 ng/g lipid weight, respectively), suggesting a biomagnification potential for HBCDs. Relatively low HBCD concentrations were reported in the few human studies conducted to date (median values varied between 0.35 and 1.1 ng/g lipid weight). HBCD levels in biota are increasing slowly and seem to reflect the local market demand. One important observation is the shift from the high percentage of the gamma-HBCD stereoisomer in the technical products to a dominance of the alpha-HBCD stereoisomer in biological samples. A combination of factors such as variations in solubility, partitioning behavior, uptake, and, possibly, selective metabolism of individual isomers may explain the observed changes in stereoisomer patterns. Recommendations for further work include research on how HBCDs are transferred from products into the environment upon production, use, and disposal. Time trends need to be analyzed more in detail, including HBCD stereoisomers, and more data on terrestrial organisms are needed, especially for humans. Whenever possible, HBCDs should be analyzed as individual stereoisomers in order to address their fate and effects

Inhibition of an Alzheimer's disease-associated form of necroptosis rescues neuronal death in mouse models.

Necroptosis is a regulated form of cell death that has been observed in Alzheimer's disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)-Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as "GVD-necroptosis" may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD

Thirteen years of monitoring selected biomarkers in Eelpout ( Zoarces viviparus

Several biomarkers in female and male eelpout (Zoarces viviparus) were measured at Fjällbacka, a reference site on the Swedish west coast from 1989 to 2001. Standardised procedures for sampling and measurements were used. Some of the biomarkers were largely stable through the years, for example, condition factor, blood plasma chloride concentration, white blood cell count, percentage of lymphocytes, activities of glutathione-S-transferase and glutathione reductase. Others showed greater variations but not significant trends, for example, percentage of granulocytes and activity of catalase and ethoxyresorufin-O-deethylase activity. Three variables in female eelpout showed a statistically significant downward trend from 1989 to 2001, hematocrit, body weight and length. The change in hematocrit was probably related to decreased stress due to improved sampling techniques, but the reason for changes in weight and length remain unknown. There is a need to evaluate the area for pollutants. The results indicate that there have not been any major large-scale changes in the aquatic environment affecting the fish health at the investigated sit

Influence of season and pollution on the antioxidant defenses of the cichlid fish acará (Geophagus brasiliensis)

The livers of Geophagus brasiliensis collected from both a non-polluted site and a polluted site were analyzed for different antioxidant defenses, O2 consumption, thiobarbituric acid-reactive substance (TBARS) levels, and histological damage. Compared to controls (116.6 ± 26.1 nmol g-1), TBARS levels were enhanced at the polluted site (284.2 ± 25.6 nmol g-1), as also was oxygen consumption (86.6 ± 11.3 and 128.5 ± 9.8 µmol O2 min-1 g-1, respectively). With respect to enzymatic antioxidants, increased catalase activities (8.7 ± 1.3 and 29.2 ± 2.4 mmol min-1 g-1, respectively), unchanged superoxide dismutase activities (767.2 ± 113.3 and 563.3 ± 70.2 U g-1, respectively), and diminished glutathione S-transferase activities (29.0 ± 3.2 and 14.9 ± 3.2 µmol min-1 g-1, respectively) were detected. Reduced glutathione (1.91 ± 0.17 and 1.37 ± 0.25 mM, respectively), oxidized glutathione (1.50 ± 0.20 and 0.73 ± 0.17 mM, respectively), and total glutathione (3.40 ± 0.26 and 2.07 ± 0.27 mM, respectively) concentrations were also below control values at the polluted site. Nevertheless, the observed ethoxyresorufin-O-deethylase activities (1.34 ± 0.11 and 16.7 ± 0.21 pmol min-1 mg-1, respectively) showed enhanced values at the polluted site. The main histological damage observed in the hepatocytes from fish collected at the polluted site was characterized by heavy lipid infiltration. Fish collected at the end of spring showed higher O2 consumption, higher superoxide dismutase and glutathione S-transferase activities, and higher total and oxidized glutathione concentrations compared to the beginning of autumn. No seasonal changes were observed in catalase activities, glutathione or TBARS levels. Fish chronically exposed to relatively high pollution levels seem to be unable to set up adequate antioxidant defenses, probably due to severe injury to their hepatocytes. The higher antioxidant defenses found at the end of spring are probably related to the enhanced activities during high temperature periods in thermoconforming organisms