Sodium-glucose co-transporter-2 inhibitors are associated with kidney benefits at all degrees of albuminuria: A retrospective cohort study of adults with diabetes.

AIM: To estimate the real-world effectiveness of sodium-glucose co-transporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) at reducing loss of kidney function and adverse kidney events in adults with varying levels of albuminuria. MATERIALS AND METHODS: In this retrospective cohort study using administrative data, we matched new SGLT2i users 1:2 to DPP4i users on diabetes therapy, chronic kidney disease (CKD) stage, albuminuria and time-conditional propensity score. Albuminuria was defined by spot urine albumin or equivalent as mild, moderate or severe. Linear regression was used to model the estimated glomerular filtration rate (eGFR), and Poisson regression for a composite kidney outcome (> 40% loss of eGFR, kidney replacement therapy or death from kidney causes) and all-cause mortality. RESULTS: SGLT2i users (n = 19 238, median age 57.9 years, female 40.9%) had mostly nil/mild albuminuria (70.7%). SGLT2is were associated with a 1.36 (95% CI 0.98-1.74) mL/min/1.73m2 (P < .001) acute (≤ 60 days) decline in eGFR, relative to DPP4is. Thereafter, SGLT2is were associated with 1.04 (95% CI 0.93-1.15) mL/min/1.73m2 (P < .001) less annual eGFR loss. SGLT2i users had fewer adverse kidney outcomes (incidence rate ratio [IRR] 0.58 [0.47-0.71]; P < .001), but not all-cause mortality (IRR 0.82 [0.66-1.01]; P = .06). Outcomes were similar considering only those with nil/mild albuminuria. CONCLUSIONS: SGLT2is may prevent eGFR decline and reduce the risk of adverse kidney events in adults with diabetes and nil or non-severe albuminuria.

Effects of dietary 2-(2H-benzotriazol-2-yl)-4-methylphenol (UV-P) exposure on Japanese medaka (Oryzias latipes) in a short-term reproduction assay.

Benzotriazole ultraviolet stabilizers (BZT-UVs) are added to various products to prevent damage caused by UV light and have emerged as contaminants of concern. Although BZT-UVs are detected in aquatic biota globally, few studies have assessed their potential toxic effects. The objective of the present study was to assess effects of 2-(2H-Benzotriazol-2-yl)-4-methylphenol (UV-P) on reproductive success of Japanese medaka (Oryzias latipes) in a standard 21-day reproduction assay. Japanese medaka were exposed to dietary UV-P at concentrations of 0, 36, 158, and 634 ng UV-P/g food, for a total of 28 days which included 7 days of exposure prior to the start of the 21-day reproduction assay. No significant effect on egg production or fertilization success was observed. Abundances of transcripts of erα, vtgI, cyp1a, or cyp3a4 were not significantly different in livers from male or female fish exposed to UV-P. However, abundances of transcripts of cyp11a and cyp19a were significantly lower in gonads from female fish. There was a trend of increasing concentrations of E2 and a non-significant increase of T in the 634 ng/g treatment in plasma from female fish exposed to UV-P. Concentrations of 11-KT were unchanged in plasma from males exposed to UV-P. These responses suggest weak perturbation of steroidogenesis, consistent with an antiandrogenic mode of action. However, this perturbation was insufficient to impair reproductive performance. Metabolomics analysis of female livers suggests altered concentrations of various metabolites and biological pathways, including glutathione metabolism, suggesting that UV-P might cause responses related to oxidative stress or phase II metabolism. However, metabolomics revealed no obvious mechanism of toxicity. Overall, results of this study indicate that dietary exposure to UV-P up to 634 ng/g food does not significantly impact reproductive performance of Japanese medaka but impacts on steroidogenesis could indicate a potential mechanism of toxicity which might lead to reproductive impairment in more sensitive species.

Inhibition of Oocyte Maturation by Malathion and Structurally Related Chemicals in Zebrafish (Danio rerio) After In Vitro and In Vivo Exposure.

Oogenesis is the process by which a primary oocyte develops into a fertilizable oocyte, making it critical to successful reproduction in fish. In zebrafish (Danio rerio), there are five stages of oogenesis. During the final step (oocyte maturation), the maturation-inducing hormone 17α,20ß-dihydroxy-4-pregnen-3-one (MIH) activates the membrane progestin receptor, inducing germinal vesicle breakdown. Using in vitro assays, it has been shown that anthropogenic stressors can dysregulate MIH-induced oocyte maturation. However, it is unknown whether the in vitro assay is predictive of reproductive performance after in vivo exposure. We demonstrate that a known inhibitor of oocyte maturation, malathion, and a structurally related chemical, dimethoate, inhibit oocyte maturation. However, malaoxon and omethoate, which are metabolites of malathion and dimethoate, did not inhibit oocyte maturation. Malathion and dimethoate inhibited maturation to a similar magnitude when oocytes were exposed for 4 h in vitro or 10 days in vivo, suggesting that the in vitro zebrafish oocyte maturation assay might be predictive of alterations to reproductive performance. However, when adult zebrafish were exposed to malathion for 21 days, there was no alteration in fecundity or fertility in comparison with control fish. Our study supports the oocyte maturation assay as being predictive of the success of in vitro oocyte maturation after in vivo exposure, but it remains unclear whether inhibition of MIH-induced oocyte maturation in vitro correlates to decreases in reproductive performance. Environ Toxicol Chem 2022;41:1381-1389. © 2022 SETAC.

1H NMR based metabolomic profiling of early life stage zebrafish (Danio rerio) exposed to a water-soluble fraction of weathered sediment-bound diluted bitumen.

Spills of diluted bitumen (dilbit) from pipelines pose a risk to the health of aquatic organisms, including fish, and with expected increases in production and transportation of dilbit, these risks could increase. To date, the majority of studies have investigated effects of fresh dilbit on aquatic organisms, but little is known about effects of weathered sediment-bound dilbit, including mechanisms of toxicity. The goal of this study was to use 1H NMR based metabolomics to identify altered metabolites and pathways in early life-stages of zebrafish (Danio rerio) exposed to a sediment derived water-soluble fraction of dilbit (SDWSF) to better understand mechanisms of adverse effects. Zebrafish embryos exposed to the SDWSF until 120 h post-fertilization exhibited increased prevalence of pericardial edema, yolk sac edema, and swim bladder malformations that are typical of exposure to fresh dilbit. Concentrations of nine metabolites (alanine, glutamine, lysine, threonine, tyrosine, betaine, taurine, inosine, and glycerol) were significantly altered in embryos exposed to SDWSF. Pathway topology analysis revealed four potentially impacted pathways: 1) phenylalanine, tyrosine, and tryptophan biosynthesis, 2) taurine and hypotaurine metabolism, 3) alanine, aspartate, and glutamate metabolism, and 4) glycine, serine, and threonine metabolism. Altered metabolites were linked to several biological process, that when perturbed could be key events in mechanisms of developmental effects observed in embryos. Future studies should further investigate the role of perturbations to these metabolites and pathways to determine the specific role they might play in adverse effects of exposure to dilbit.

Toxicity of Weathered Sediment-Bound Dilbit to Early Life Stages of Zebrafish (Danio rerio).

Due to high viscosity, bitumen extracted from the Alberta oil sands is diluted with natural gas condensates to form diluted bitumen (dilbit) to facilitate transport through pipelines. Dilbit that is spilled into or near a waterbody is subject to environmental weathering processes such as evaporation and interaction with sediments. This is the first study that assessed the toxicity of weathered sediment-bound dilbit (WSD) to fish early life stages. Exposure of zebrafish (Danio rerio) embryos to water-soluble fractions (WSFs) or water-accommodated fractions (WAFs) of WSD from 30 min to 120 h postfertilization resulted in pericardial edema, yolk sac edema, and incidences of uninflated swim bladder. The presence of oil-mineral aggregates (OMAs) in the WAFs greatly increased toxicity, despite all fractions having similar concentrations of dissolved polycyclic aromatic hydrocarbons (PAHs). There were greater cyp1a mRNA abundances in larvae exposed to WAFs, suggesting that there were differences in bioavailability of PAHs between fractions. However, there was little evidence that embryotoxicity was caused by oxidative stress. Results suggest that evaporation and sediment interaction do not completely attenuate toxicity of dilbit to zebrafish early life stages, and OMAs in exposures exacerbate toxicity.