Identification of the xenometabolome and novel contaminant markers in fish exposed to a wastewater treatment works effluent

Fish can bioconcentrate complex mixtures of xenobiotics arising from exposure to wastewater effluents discharged into surface waters. Wastewaters contain a complex mixture of organic compounds and little is known about their uptake into fish and their health effects. In this study, a chemical profiling approach was used to characterize the profile of xenobiotics and their metabolites (the xenometabolome) in biofluids (bile and plasma) of juvenile rainbow trout (Oncorhynchus mykiss) exposed to a wastewater effluent. Metabolite profiles of effluent-exposed fish were compared with that from control fish exposed to uncontaminated river water. Samples were analysed by ultra performance liquid chromatography-time-of-flight mass spectrometry and data analysed by multivariate statistics. Exposure to effluent resulted in accumulation in trout bile of alkylsulfophenyl and alkylpolyethoxy carboxylates, as well as glucuronide conjugates of nonylphenol ethoxylates, alcohol ethoxylates, naphthols, chlorinated xylenols and phenoxyphenols, chlorophenes, resin acids, mefenamic acid and oxybenzone. Nonconjugated or sulphate conjugates of many of these contaminants were also detected in plasma of effluent-exposed trout. In addition, changes in the concentrations of endogenously derived metabolites were also detected in trout plasma, and these included an increase in blood bile acids, methylbutryolcarnitine and a decrease in sphingosine levels. These observations were verified in a further exposure of sexually mature roach (Rutilus rutilus) to concentrations of the same effluent. Exposure to 50% or 100% effluent resulted in dose dependent increases in blood concentrations of xenobiotics, taurocholic acid, syprinol sulphate and lysophospholipids and decreases in sphingosine levels. This work reveals the complex nature of xenobiotics accumulating in effluent-exposed fish together with the identification of changes in concentrations of lipid metabolites associated with hepatotoxicity. These results reveal, for the first time, that metabolite profiling techniques can be used to screen for uptake of complex mixtures of contaminants into fish and also for the detection of natural metabolite pathways in the organism that are disrupted due to exposure to multiple xenobiotics

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Global metabolite profiling reveals transformation pathways and novel metabolomic responses in Solea senegalensis after exposure to a non-ionic surfactant

Alcohol polyethoxylate (AEO) surfactants are widely used in household and industrial products, but the health effects arising from short-term exposure to sublethal concentrations are unknown. A metabolomic approach was used to investigate the biotransformation and effects of exposure to sublethal concentrations of hexaethylene glycol monododecylether (C12EO6) in juvenile sole, Solea senegalensis. After 5 days, C12EO6 was rapidly metabolized in the sole by oxidation, glucuronidation, and ethoxylate chain shortening. C12EO6 exposure at either 146 or 553 mu g L-1 resulted in significant metabolite disruption in liver and blood samples, including an apparent fold increase of >10(6) in the circulating levels of C-24 bile acids and C-27 bile alcohols, disturbance of glucocorticoid and lipid metabolism, and a 470-fold decrease in levels of the fatty acid transport molecule palmitoyl carnitine. Depuration resulted in rapid elimination of the surfactant and normalization of metabolites toward pre-exposure levels. Our findings show for the first time the ability of metabolomic analyses to discern effects of this AEO on metabolite homeostasis at exposure levels below its no effect concentrations for survival and reproduction in juvenile fish. The pronounced alteration in levels of liver metabolites, phospholipids, and glucocorticoids in S. senegalensis in response to surfactant exposure may indicate that this contaminant could potentially impact a number of health end points in fish