Leucokinin mimetic elicits aversive behavior in mosquito Aedes aegypti (L.) and inhibits the sugar taste neuron.

Insect kinins (leucokinins) are multifunctional peptides acting as neurohormones and neurotransmitters. In females of the mosquito vector Aedes aegypti (L.), aedeskinins are known to stimulate fluid secretion from the renal organs (Malpighian tubules) and hindgut contractions by activating a G protein-coupled kinin receptor designated "Aedae-KR." We used protease-resistant kinin analogs 1728, 1729, and 1460 to evaluate their effects on sucrose perception and feeding behavior. In no-choice feeding bioassays (capillary feeder and plate assays), the analog 1728, which contains α-amino isobutyric acid, inhibited females from feeding on sucrose. It further induced quick fly-away or walk-away behavior following contact with the tarsi and the mouthparts. Electrophysiological recordings from single long labellar sensilla of the proboscis demonstrated that mixing the analog 1728 at 1 mM with sucrose almost completely inhibited the detection of sucrose. Aedae-KR was immunolocalized in contact chemosensory neurons in prothoracic tarsi and in sensory neurons and accessory cells of long labellar sensilla in the distal labellum. Silencing Aedae-KR by RNAi significantly reduced gene expression and eliminated the feeding-aversion behavior resulting from contact with the analog 1728, thus directly implicating the Aedae-KR in the aversion response. To our knowledge, this is the first report that kinin analogs modulate sucrose perception in any insect. The aversion to feeding elicited by analog 1728 suggests that synthetic molecules targeting the mosquito Aedae-KR in the labellum and tarsi should be investigated for the potential to discover novel feeding deterrents of mosquito vectors.

Mapping chemical footprints of organic micropollutants in European streams.

There is increasing awareness that chemical pollution of freshwater systems with complex mixtures of chemicals from domestic sources, agriculture and industry may cause a substantial chemical footprint on water organisms, pushing aquatic ecosystems outside the safe operating space. The present study defines chemical footprints as the risk that chemicals or chemical mixtures will have adverse effects on a specific group of organisms. The aim is to characterise these chemical footprints in European streams based on a unique and uniform screening of more than 600 chemicals in 445 surface water samples, and to derive site- and compound-specific information for management prioritisation purposes. In total, 504 pesticides, biocides, pharmaceuticals and other compounds have been detected, including frequently occurring and site-specific compounds with concentrations up to 74 µg/L. Key finding is that three-quarter of the investigated sites in 22 European river basins exceed established thresholds for chemical footprints in freshwater, leading to expected acute or chronic impacts on aquatic organisms. The largest footprints were recorded on invertebrates, followed by algae and fish. More than 70 chemicals exceed thresholds of chronic impacts on invertebrates. For all organism groups, pesticides and biocides were the main drivers of chemical footprints, while mixture impacts were particularly relevant for invertebrates. No clear significant correlation was found between chemical footprints and the urban discharge fractions, suggesting that effluent-specific quality rather than the total load of treated wastewater in the aquatic environment and the contribution of diffuse sources, e.g. from agriculture, determine chemical footprints.

Prediction of Molecular Initiating Events for Adverse Outcome Pathways Using High-Throughput Identification of Chemical Targets.

The impact of exposure to multiple chemicals raises concerns for human and environmental health. The adverse outcome pathway method offers a framework to support mechanism-based assessment in environmental health starting by describing which mechanisms are triggered upon interaction with different stressors. The identification of the molecular initiating event and the molecular interaction between a chemical and a protein target is still a challenge for the development of adverse outcome pathways. The cellular response to chemical exposure studied with omics could not directly identify the protein targets. However, recent mass spectrometry-based methods are offering a proteome-wide identification of protein targets interacting with s but unrevealing a molecular initiating event from a set of targets is still dependent on available knowledge. Here, we directly coupled the target identification findings from the proteome integral solubility alteration assay with an analytical hierarchy process for the prediction of a prioritized molecular initiating event. We demonstrate the applicability of this combination of methodologies with a test compound (TCDD), and it could be further studied and integrated into AOPs. From the eight protein targets identified by the proteome integral solubility alteration assay after analyzing 2824 human hepatic proteins, the analytical hierarchy process can select the most suitable protein for an AOP. Our combined method solves the missing links between high-throughput target identification and prediction of the molecular initiating event. We anticipate its utility to decipher new molecular initiating events and support more sustainable methodologies to gain time and resources in chemical assessment.

Endocrine disrupting chemicals entering European rivers: Occurrence and adverse mixture effects in treated wastewater.

In the present study on endocrine disrupting chemicals (EDCs) in treated wastewater, we used chemical and effect-based tools to analyse 56 wastewater treatment plant (WWTP) effluents from 15 European countries. The main objectives were (i) to compare three different receptor-based estrogenicity assays (ERα-GeneBLAzer, p-YES, ERα-CALUX®), and (ii) to investigate a combined approach of chemical target analysis and receptor-based testing for estrogenicity, glucocorticogenic activity, androgenicity and progestagenic activity (ERα-, GR-, AR- and PR-GeneBLAzer assays, respectively) in treated wastewater. A total of 56 steroids and phenols were detected at concentrations ranging from 25 pg/L (estriol, E3) up to 2.4 µg/L (cortisone). WWTP effluents, which passed an advanced treatment via ozonation or via activated carbon, were found to be less contaminated, in terms of lower or no detection of steroids and phenols, as well as hormone receptor-mediated effects. This result was confirmed by the effect screening, including the three ERα-bioassays. In the GeneBLAzer assays, ERα-activity was detected in 82 %, and GR-activity in 73 % of the samples, while AR- and PR-activity were only measured in 14 % and 21 % of the samples, respectively. 17ß-estradiol was confirmed as the estrogen dominating the observed estrogenic mixture effect and triamcinolone acetonide was the dominant driver of glucocorticogenic activity. The comparison of bioanalytical equivalent concentrations (BEQ) predicted from the detected concentrations and the relative effect potency (BEQchem) with measured BEQ (BEQbio) demonstrated good correlations of chemical target analysis and receptor-based testing results with deviations mostly within a factor of 10. Bioassay-specific effect-based trigger values (EBTs) from the literature, but also newly calculated EBTs based on previously proposed derivation options, were applied and allowed a preliminary assessment of the water quality of the tested WWTP effluent samples. Overall, this study demonstrates the high potential of linking chemical with effect-based analysis in water quality assessment with regard to EDC contamination.

A risk based assessment approach for chemical mixtures from wastewater treatment plant effluents.

In this study, 56 effluent samples from 52 European wastewater treatment plants (WWTPs) were investigated for the occurrence of 499 emerging chemicals (ECs) and their associated potential risks to the environment. The two main objectives were (i) to extend our knowledge on chemicals occurring in treated wastewater, and (ii) to identify and prioritize compounds of concern based on three different risk assessment approaches for the identification of consensus mixture risk drivers of concern. Approaches include (i) PNEC and EQS-based regulatory risk quotients (RQs), (ii) species sensitivity distribution (SSD)-based hazard units (HUs) and (iii) toxic units (TUs) for three biological quality elements (BQEs) algae, crustacean, and fish. For this purpose, solid-phase extracts were analysed with wide-scope chemical target screening via liquid chromatography high-resolution mass spectrometry (LC-HRMS), resulting in 366 detected compounds, with concentrations ranging from < 1 ng/L to > 100 µg/L. The detected chemicals were categorized with respect to critical information relevant for risk assessment and management prioritization including: (1) frequency of occurrence, (2) measured concentrations, (3) use groups, (4) persistence & bioaccumulation, and (5) modes of action. A comprehensive assessment using RQ, HU and TU indicated exceedance of risk thresholds for the majority of effluents with RQ being the most sensitive metric. In total, 299 out of the 366 compounds were identified as mixture risk contributors in one of the approaches, while 32 chemicals were established as consensus mixture risk contributors of high concern, including a high percentage (66%) of pesticides and biocides. For samples which have passed an advanced treatment using ozonation or activated carbon (AC), consistently much lower risks were estimated.

Emerging Roles of Hydrogen Sulfide in Inflammatory and Neoplastic Colonic Diseases.

Hydrogen sulfide (H2S) is a toxic gas that has been recognized as an important mediator of many physiological processes, such as neurodegeneration, regulation of inflammation, blood pressure, and metabolism. In the human colon, H2S is produced by both endogenous enzymes and sulfate-reducing bacteria (SRB). H2S is involved in the physiological and pathophysiological conditions of the colon, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), which makes the pharmacological modulation of H2S production and metabolism a potential chemical target for the treatment of colonic diseases. However, the exact mechanisms and pathways by which H2S-mediates normal physiological function and disease in the colon are not fully understood. Besides, the production and release of H2S are modulated by both endogenous and exogenous factors. This review will discuss the production and storage of H2S, its biological roles and the emerging importance in physiology and pathology of IBD and CRC.