Resistance as a factor in environmental exposure of anticoagulant rodenticides: a modelling approach

Anticoagulant rodenticide (AR) resistance in Norway rat populations has been a problem for fifty years, however its impact on non-target species, particularly predatory and scavenging animals has received little attention. Field trials were conducted on farms in Germany and England where resistance to anticoagulant rodenticides had been confirmed. Resistance is conferred by different mutations of the VKORC1 gene in each of these regions: tyrosine139cysteine in Germany and leucine120glutamine in England. A modelling approach was used to study the transference of the anticoagulants into the environment during treatments for Norway rat control. Baiting with brodifacoum resulted in lower levels of AR entering the food chain via the rats and lower numbers of live rats carrying residues during and after the trials due to its lower application rate and efficacy against resistant rats. Bromadiolone and difenacoum resulted in markedly higher levels of AR uptake into the rat population and larger numbers of live rats carrying residues during the trials and for long periods after the baiting period. Neither bromadiolone nor difenacoum provided full control on any of the treated farms. In resistant areas where ineffective compounds are used there is the potential for higher levels of AR exposure to non-target animals, particularly predators of rats and scavengers of rat carcasses. Thus, resistance influences the total amount of AR available to non-targets and should be considered when dealing with rat infestations, as resistance-breakers may present a lower risk to wildlife.

Evidence for interplay between genes and maternal stress in utero: monoamine oxidase A polymorphism moderates effects of life events during pregnancy on infant negative emotionality at 5 weeks

The low activity variant of the monoamine oxidase A (MAOA) functional promoter polymorphism, MAOA-LPR, in interaction with adverse environments (G × E) is associated with child and adult antisocial behaviour disorders. MAOA is expressed during foetal development so in utero G × E may influence early neurodevelopment. We tested the hypothesis that MAOA G × E during pregnancy predicts infant negative emotionality soon after birth. In an epidemiological longitudinal study starting in pregnancy, using a two stage stratified design, we ascertained MAOA-LPR status (low vs. high activity variants) from the saliva of 209 infants (104 boys and 105 girls), and examined predictions to observed infant negative emotionality at 5 weeks post-partum from life events during pregnancy. In analyses weighted to provide estimates for the general population, and including possible confounders for life events, there was an MAOA status by life events interaction (P = 0.017). There was also an interaction between MAOA status and neighbourhood deprivation (P = 0.028). Both interactions arose from a greater effect of increasing life events on negative emotionality in the MAOA-LPR low activity, compared with MAOA-LPR high activity infants. The study provides the first evidence of moderation by MAOA-LPR of the effect of the social environment in pregnancy on negative emotionality in infancy, an early risk for the development of child and adult antisocial behaviour disorders.

Assessment of plant uptake models used in exposure assessment tools for soils contaminated with organic pollutants

The aim of this study was to evaluate and improve the accuracy of plant uptake models for neutral hydrophobic organic pollutants (1 < logKOW < 9, −8 < logKAW < 0) used in regulatory exposure assessment tools, using uncertainty and sensitivity analyses. The models considered were RAIDAR, EUSES, CSOIL, CLEA, and CalTOX. In this research, CSOIL demonstrated the best performance of all five exposure assessment tools for root uptake from polluted soil in comparison with observed data, but no model predicted shoot uptake well. Recalibration of the transpiration and volatilisation parameters improved the performance of CSOIL and CLEA. The dominant pathway for shoot uptake simulated differed according to the properties of the chemical under consideration; those with a higher air–water partition coefficient were transported into shoots via the soil-air-plant pathway, while chemicals with a lower octanol–water partition coefficient and air–water partition coefficient were transported via the root. The soil organic carbon content was a particularly sensitive parameter in each model and using a site specific value improved model performance.

Assessment and improvement of biotransfer models to cow’s milk and beef used in exposure assessment tools for organic pollutants

The aim of this study was to assess and improve the accuracy of biotransfer models for the organic pollutants (PCBs, PCDD/Fs, PBDEs, PFCAs, and pesticides) into cow’s milk and beef used in human exposure assessment. Metabolic rate in cattle is known as a key parameter for this biotransfer, however few experimental data and no simulation methods are currently available. In this research, metabolic rate was estimated using existing QSAR biodegradation models of microorganisms (BioWIN) and fish (EPI-HL and IFS-HL). This simulated metabolic rate was then incorporated into the mechanistic cattle biotransfer models (RAIDAR, ACC-HUMAN, OMEGA, and CKow). The goodness of fit tests showed that RAIDAR, ACC-HUMAN, OMEGA model performances were significantly improved using either of the QSARs when comparing the new model outputs to observed data. The CKow model is the only one that separates the processes in the gut and liver. This model showed the lowest residual error of all the models tested when the BioWIN model was used to represent the ruminant metabolic process in the gut and the two fish QSARs were used to represent the metabolic process in the liver. Our testing included EUSES and CalTOX which are KOW-regression models that are widely used in regulatory assessment. New regressions based on the simulated rate of the two metabolic processes are also proposed as an alternative to KOW-regression models for a screening risk assessment. The modified CKow model is more physiologically realistic, but has equivalent usability to existing KOW-regression models for estimating cattle biotransfer of organic pollutants.

Organic pollutants in animal products

It is necessary to assess the contamination of animal products by pollutants in order to protect human health. This can be achieved by understanding the processes whereby contaminants are introduced into the food chain. Such contamination can arise from the atmospheric deposition on to crops and soil or via contaminated feed. These processes are described and quantified with particular reference to the deposition of organic pollutants onto pasture. The transfer of the contaminants from the fodder and feed to the animal is also described. Finally, these processes are put in context by the illustration of how they are used in regulatory exposure models.

Human exposure modelling for chemical risk assessment: a review of current approaches and research and policy implications

A wide variety of exposure models are currently employed for health risk assessments. Individual models have been developed to meet the chemical exposure assessment needs of Government, industry and academia. These existing exposure models can be broadly categorised according to the following types of exposure source: environmental, dietary, consumer product, occupational, and aggregate and cumulative. Aggregate exposure models consider multiple exposure pathways, while cumulative models consider multiple chemicals. In this paper each of these basic types of exposure model are briefly described, along with any inherent strengths or weaknesses, with the UK as a case study. Examples are given of specific exposure models that are currently used, or that have the potential for future use, and key differences in modelling approaches adopted are discussed. The use of exposure models is currently fragmentary in nature. Specific organisations with exposure assessment responsibilities tend to use a limited range of models. The modelling techniques adopted in current exposure models have evolved along distinct lines for the various types of source. In fact different organisations may be using different models for very similar exposure assessment situations. This lack of consistency between exposure modelling practices can make understanding the exposure assessment process more complex, can lead to inconsistency between organisations in how critical modelling issues are addressed (e.g. variability and uncertainty), and has the potential to communicate mixed messages to the general public. Further work should be conducted to integrate the various approaches and models, where possible and regulatory remits allow, to get a coherent and consistent exposure modelling process. We recommend the development of an overall framework for exposure and risk assessment with common approaches and methodology, a screening tool for exposure assessment, collection of better input data, probabilistic modelling, validation of model input and output and a closer working relationship between scientists and policy makers and staff from different Government departments. A much increased effort is required is required in the UK to address these issues. The result will be a more robust, transparent, valid and more comparable exposure and risk assessment process. (C) 2006 Elsevier Ltd. All rights reserved.

Organizational effects of fetal testosterone on human corpus callosum size and asymmetry

Previous theory and research in animals has identified the critical role that fetal testosterone (FT) plays in organizing sexually dimorphic brain development. However, to date there are no studies in humans directly testing the organizational effects of FT on structural brain development. In the current study we investigated the effects of FT on corpus callosum size and asymmetry. High-resolution structural magnetic resonance images (MRI) of the brain were obtained on 28 8-11-year-old boys whose exposure to FT had been previously measured in utero via amniocentesis conducted during the second trimester. Although there was no relationship between FT and midsaggital corpus callosum size, increasing FT was significantly related to increasing rightward asymmetry (e.g., Right>Left) of a posterior subsection of the callosum, the isthmus, that projects mainly to parietal and superior temporal areas. This potential organizational effect of FT on rightward callosal asymmetry may be working through enhancing the neuroprotective effects of FT and result in an asymmetric distribution of callosal axons. We suggest that this possible organizational effect of FT on callosal asymmetry may also play a role in shaping sexual dimorphism in functional and structural brain development, cognition, and behavior.

Developmental programming: Deficits in reproductive hormone dynamics and ovulatory outcomes in prenatal, testosterone-treated sheep

Prenatal testosterone excess leads to neuroendocrine, ovarian, and metabolic disruptions, culminating in reproductive phenotypes mimicking that of women with polycystic ovary syndrome (PCOS). The objective of this study was to determine the consequences of prenatal testosterone treatment on periovulatory hormonal dynamics and ovulatory outcomes. To generate prenatal testosterone-treated females, pregnant sheep were injected intramuscularly (days 30-90 of gestation, term = 147 days) with 100 mg of testosterone-propionate in cottonseed oil semi-weekly. Female offspring born to untreated control females and prenatal testosterone-treated females were then studied during their first two breeding seasons. Sheep were given two injections of prostaglandin F-2alpha 11 days apart, and blood samples were collected at 2-h intervals for 120 h, 10-min intervals for 8 h during the luteal phase (first breeding season only), and daily for an additional 15 days to characterize changes in reproductive hormonal dynamics. During the first breeding season, prenatal testosterone-treated females manifested disruptions in the timing and magnitude of primary gonadotropin surges, luteal defects, and reduced responsiveness to progesterone negative feedback. Disruptions in the periovulatory sequence of events during the second breeding season included: 1) delayed but increased preovulatory estradiol rise, 2) delayed and severely reduced primary gonadotropin surge in prenatal testosterone-treated females having an LH surge, 3) tendency for an amplified secondary FSH surge and a shift in the relative balance of FSH regulatory proteins, and 4) luteal responses that ranged from normal to anovulatory. These outcomes are likely to be of relevance to developmental origin of infertility disorders and suggest that differences in fetal exposure or fetal susceptibility to testosterone may account for the variability in reproductive phenotypes.

Effects of dredging in Goteborg Harbor, Sweden, assessed by biomarkers in eelpout (Zoarces viviparus)

We used a battery of biomarkers in fish to study the effects of the extensive dredging in Goteborg harbor situated at the river Gota alv estuary, Sweden. Eelpout (Zoarces viviparus) were sampled along a gradient into Goteborg harbor, both before and during the dredging. Biomarker responses in the eelpout before the dredging already indicated that fish in Goteborg harbor are chronically affected by pollutants under normal conditions compared to those in a reference area. However, the results during the dredging activities clearly show that fish were even more affected by remobilized pollutants. Elevated ethoxyresorufin-O-deethylase activities and cytochrome P4501A levels indicated exposure to polycyclic aromatic hydrocarbons. Elevated metallothionein gene expression indicated an increase in metal exposure. An increase in general cell toxicity, measured as a decrease in lysosomal membrane stability, as well as effects on the immune system also could be observed in eelpout sampled during the dredging. The results also suggest that dredging activities in the Gota alv estuary can affect larger parts of the Swedish western coast than originally anticipated. The present study demonstrates that the application of a set of biomarkers is a useful approach in monitoring the impact of anthropogenic activities on aquatic environments.

Amino terminal interaction in the prion protein identified using fusion to green fluorescent protein

In contrast to the well-characterized carboxyl domain, the amino terminal half of the mature cellular prion protein has no defined structure. Here, following fusion of mouse prion protein fragments to green fluorescence protein as a reporter of protein stability, we report extreme variability in fluorescence level that is dependent on the prion fragment expressed. In particular, exposure of the extreme amino terminus in the context of a truncated prion protein molecule led to rapid degradation, whereas the loss of only six amino terminal residues rescued high level fluorescence. Study of the precise endpoints and residue identity associated with high fluorescence suggested a domain within the amino terminal half of the molecule defined by a long-range intramolecular interaction between 23KKRPKP28 and 143DWED146 and dependent upon the anti-parallel beta-sheet ending at residue 169 and normally associated with the structurally defined carboxyl terminal domain. This previously unreported interaction may be significant for understanding prion bioactivity and for structural studies aimed at the complete prion structure.

Modulation of detoxification enzymes by watercress: in vitro and in vivo investigations in human peripheral blood cells

Epidemiological studies indicate that consumption of cruciferous vegetables (CV) can reduce the risk of cancer. Supposed mechanisms are partly the inhibition of phase I and the induction of phase II enzymes. The aim of this study was to investigate in vitro and in vivo effects of watercress (WC), a member of the CV family, on chemopreventive parameters using human peripheral blood mononuclear cells (PBMC) as surrogate cells. We investigated the hypothesis that WC reduces cancer risk by inducing detoxification enzymes in a genotype-dependent manner. In vitro gene expression and enzyme activity experiments used PBMC incubated with a crude extract from fresh watercress (WCE, 0.1-10 mu L/mL with 8.2 g WC per 1 mL extract) or with one main key compound phenethyl isothiocyanate (PEITC, 1-10 mu M). From an in vivo perspective, gene expression and glutathione S-transferase (GST) polymorphisms were determined in PBMC obtained from a human intervention study in which subjects consumed 85 g WC per day for 8 weeks. The influence of WC consumption on gene expression was determined for detoxification enzymes such as superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPX1), whilst the SOD and GPX activities in red blood cells were also analysed with respect to GST genotypes. In vitro exposure of PBMC to WCE or PEITC (24 h) increased gene expression for both detoxification enzymes GPX1 (5.5-fold, 1 mu L/mL WCE, 3.7-fold 1 mu M PEITC) and SOD2 (12.1-fold, 10 mu L/mL WCE, 7.3-fold, 10 mu M PEITC), and increased SOD2 activity (1.9-fold, 10 mu L/mL WCE). The WC intervention had no significant effect on in vivo PBMC gene expression, as high individual variations were observed. However, a small but significant increase in GPX (p = 0.025) and SOD enzyme activity (p = 0.054) in red blood cells was observed in GSTM1*0, but not in GSTM1*1 individuals, whilst the GSTT1 genotype had no impact. The results indicate that WC is able to modulate the enzymes SOD and GPX in blood cells in vitro and in vivo, and suggest that the capacity of moderate intake of CV to induce detoxification is dependent in part on the GSTM1 genotype.

Space exposure of infrared filters and materials on the NASA Long Duration Exposure Facility (LDEF)

Infrared optical-multilayer filters and materials were exposed to the space environment of low Earth for a period of nearly six years on the NASA Long Duration Exposure Facility (LDEF) mission. This report describes the effects of that environment on the physical and optical properties of filters and materials used in an experiment designed by the University of reading Infrared multilayer Laboratory. Results of the experiment comprise IR processed spectra both before (1983), and after (1990) exposure, in conjunction with unexposed control samples.

Fibroblast growth factor 2 maintains the neurogenic capacity of embryonic neural progenitor cells in vitro but changes their neuronal subtype specification

Many in vitro systems used to examine multipotential neural progenitor cells (NPCs) rely on mitogens including fibroblast growth factor 2 (FGF2) for their continued expansion. However, FGF2 has also been shown to alter the expression of transcription factors (TFs) that determine cell fate. Here, we report that NPCs from the embryonic telencephalon grown without FGF2 retain many of their in vivo characteristics, making them a good model for investigating molecular mechanisms involved in cell fate specification and differentiation. However, exposure of cortical NPCs to FGF2 results in a profound change in the types of neurons generated, switching them from a glutamatergic to a GABAergic phenotype. This change closely correlates with the dramatic upregulation of TFs more characteristic of ventral telencephalic NPCs. In addition, exposure of cortical NPCs to FGF2 maintains their neurogenic potential in vitro, and NPCs spontaneously undergo differentiation following FGF2 withdrawal. These results highlight the importance of TFs in determining the types of neurons generated by NPCs in vitro. In addition, they show that FGF2, as well as acting as a mitogen, changes the developmental capabilities of NPCs. These findings have implications for the cell fate specification of in vitro-expanded NPCs and their ability to generate specific cell types for therapeutic applications. Disclosure of potential conflicts of interest is found at the end of this article.

Differential uptake, partitioning and transfer of Cd and Zn in the soil-pea plant-aphid system

The biomagnification of trace metals during transfer from contaminated soil to higher trophic levels may potentially result in the exposure of predatory arthropods to toxic concentrations of these elements. This study examined the transfer of Cd and Zn in a soil−plant−arthropod system grown in series of field plots that had received two annual applications of municipal biosolids with elevated levels of Cd and Zn. Results showed that biosolids amendment significantly increased the concentration of Cd in the soil and the shoots of pea plants and the concentration of Zn in the soil, pea roots, shoots, and pods. In addition, the ratio of Cd to Zn concentration showed that Zn was preferentially transferred compared to Cd through all parts of the system. As a consequence, Zn was biomagnified by the system whereas Cd was biominimized. Cd and Zn are considered to exhibit similar behaviors in biological systems. However, the Cd/Zn ratios demonstrated that in this system, Cd is much less labile in the root−shoot−pod and shoot−aphid pathways than Zn.

Comparison of subcellular partitioning, distribution, and internal speciation of Cu between Cu-tolerant and naive populations of Dendrodrilus rubidus Savigny

When considering contaminated site ecology and ecological risk assessment a key question is whether organisms that appear unaffected by accumulation of contaminants are tolerant or resistant to those contaminants. A population of Dendrodrilus rubidus Savigny earthworms from the Coniston Copper Mines, an area of former Cu mining, exhibit increased tolerance and accumulation of Cu relative to a nearby non-Cu exposed population. Distribution of total Cu between different body parts (posterior, anterior, body wall) of the two populations was determined after a 14 day exposure to 250 mg Cu kg(-1) in Cu-amended soil. Cu concentrations were greater in Coniston earthworms but relative proportions of Cu in different body parts were the same between populations. Cu speciation was determined using extended X-ray absorption fine structure spectroscopy (EXAFS). Cu was coordinated to 0 atoms in the exposure soil but to S atoms in the earthworms. There was no difference in this speciation between the different earthworm populations. In another experiment earthworms were exposed to a range of Cu concentrations (200-700 mg Cu kg(-1)). Subcellular partitioning of accumulated Cu was determined. Coniston earthworms accumulated more Cu but relative proportions of Cu in the different fractions (cytosol > granular > tissue fragments, cell membranes, and intact cells) were the same between populations. Results suggest that Coniston D. rubidus are able to survive in the Cu-rich Coniston Copper Mines soil through enlargement of the same Cu storage reservoirs that exist in a nearby non-Cu exposed population.