Accumulation of Per- and Polyfluoroalkyl Substances (PFAS) in Coastal Sharks from Contrasting Marine Environments: The New York Bight and The Bahamas.

Per- and polyfluoroalkyl substances (PFAS) enter the marine food web, accumulate in organisms, and potentially have adverse effects on predators and consumers of seafood. However, evaluations of PFAS in meso-to-apex predators, like sharks, are scarce. This study investigated PFAS occurrence in five shark species from two marine ecosystems with contrasting relative human population densities, the New York Bight (NYB) and the coastal waters of The Bahamas archipelago. The total detected PFAS (∑PFAS) concentrations in muscle tissue ranged from 1.10 to 58.5 ng g-1 wet weight, and perfluorocarboxylic acids (PFCAs) were dominant. Fewer PFAS were detected in Caribbean reef sharks (Carcharhinus perezi) from The Bahamas, and concentrations of those detected were, on average, ∼79% lower than in the NYB sharks. In the NYB, ∑PFAS concentrations followed: common thresher (Alopias vulpinus) > shortfin mako (Isurus oxyrinchus) > sandbar (Carcharhinus plumbeus) > smooth dogfish (Mustelus canis). PFAS precursors/intermediates, such as 2H,2H,3H,3H-perfluorodecanoic acid and perfluorooctanesulfonamide, were only detected in the NYB sharks, suggesting higher ambient concentrations and diversity of PFAS sources in this region. Ultralong-chain PFAS (C ≥ 10) were positively correlated with nitrogen isotope values (δ15N) and total mercury in some species. Our results provide some of the first baseline information on PFAS concentrations in shark species from the northwest Atlantic Ocean, and correlations between PFAS, stable isotopes, and mercury further contextualize the drivers of PFAS occurrence.

Risk assessment for seafood consumers exposed to mercury and other trace elements in fish from Long Island, New York, USA.

We determined concentrations of Hg, Pb, Cd, Cr, As, Ni, Ag, Se, Cu, and Zn in muscle tissue of six commonly consumed Long Island fish species (black seabass, bluefish, striped bass, summer flounder, tautog, and weakfish, total sample size = 1211) caught off Long Island, New York in 2018 and 2019. Long-term consumption of these coastal fish could pose health risks largely due to Hg exposure; concentrations of the other trace elements were well below levels considered toxic for humans. By combining the measured Hg concentrations in the fish (means ranging from 0.11 to 0.27 mg/kg among the fish species), the average seafood consumption rate, and the current US EPA Hg reference dose (0.0001 mg/kg/d), it was concluded that seafood consumption should be limited to four fish meals per month for adults for some fish (bluefish, tautog) and half that for young children. Molar ratios of Hg:Se exceeded 1 for some black seabass, bluefish, tautog, and weakfish.

Effects of methylmercury on the early life stages of an estuarine forage fish using two different dietary sources.

Marine fish accumulate methylmercury (MeHg) to elevated concentrations, often higher than in freshwater systems. As a neurotoxic compound, high MeHg tissue concentrations could affect fish behavior which in turn could affect their populations. We examined the sublethal effects of MeHg on larvae of the Sheepshead minnow (Cyprinodon variegatus), an estuarine fish, using artificial or natural diets with varying MeHg concentrations (0-4.8 ppm). Larvae were fed control and MeHg-contaminated diets at low or normal (10% of their body mass) daily food rations from 7 to 29 days when they reached juvenile stage. Growth, respiration, swimming activity and prey capture ability were assessed. Food ration affected Hg toxicity in our study. Natural diets containing 3.2 ppm MeHg had no impacts on growth and swimming in fish that were fed normal food rations but depressed growth and swimming at low food rations. MeHg toxicity did not differ between artificial and natural foods, however fish accumulated more MeHg from the former. Artificial food containing 4.8 ppm MeHg only affected prey capture after 21 days of exposure. Sheepshead minnows, a forage fish species occupying a low trophic level in coastal waters, can be MeHg tolerant, especially when food is abundant, and can serve as an enriched Hg source for higher trophic level predators.

Minor effects of dietary methylmercury on growth and reproduction of the sheepshead minnow Cyprinodon variegatus and toxicity to their offspring.

Methylmercury (MeHg) is a neurotoxic compound that is found in virtually all fish and biomagnifies in aquatic food webs. Although MeHg concentrations in marine and estuarine fish are often elevated, the impacts of MeHg on marine and estuarine fish have largely been understudied. To evaluate the impact of dietary MeHg on marine fish reproduction and effects on their offspring, female juvenile sheepshead minnows (Cyprinodon variegatus) at three months of age were experimentally exposed to MeHg-contaminated diets for two months and then paired with Hg-free males for spawning. Egg production, hatching success of embryos, time to hatching, survival of larvae, growth of larvae and swimming behavior of larvae were determined. Selenium (Se) was also measured and Se/Hg molar ratios were calculated to assess whether Se reduced MeHg toxicity. MeHg had no significant impact on fish reproduction or on survival and growth of larvae. Larvae produced by MeHg-exposed mothers had concentrations of Hg about 1 ppm (dry wt), or about 12% of that in the muscle of their mothers and consistently displayed 6-15% increased swimming speed relative to controls; the ecological significance of this moderate effect on swimming speed requires further study. The Se/Hg molar ratios in these fish, which were >1 in controls (adults and larvae) and MeHg-exposed larvae but <1 in Hg-exposed adults, did not correlate with MeHg effects. The sheepshead minnow, at a low trophic level, appears to have a high tolerance of MeHg; however, it can pass MeHg to higher trophic levels in marine ecosystems where upper level predators have MeHg concentrations sometimes exceeding US FDA safety limits of 1 ppm wet wt.

An LC-MS/MS Bioanalytical Assay for the Determination of Gilteritinib in Rat Plasma and Application to a Drug-Drug Interaction Study.

BACKGROUND: Gilteritinib, a novel, potent FLT3/AXL inhibitor, was recently approved in Japan and USA for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. PURPOSE AND METHODS: In this study, we aimed to develop and validate a sensitive and simple ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantification of gilteritinib in plasma and to investigate whether CYP3A4 inhibitors (fluconazole and itraconazole) could influence the pharmacokinetics of gilteritinib from a drug-drug interaction study in rats. Sample preparation was done by a simple protein crash with acetonitrile containing the internal standard (IS) pirfenidone, followed by UPLC-MS/MS quantification. RESULTS: The assay was successfully validated in a 1-500 ng/mL calibration range for gilteritinib, where the lower limit of quantification (LLOQ) was set at 1 ng/mL. The intra-day and inter-day precisions for gilteritinib were less than 10.6%, and the accuracies were in the range of -14.5% to 11.1%. Recovery and matrix effect of the analyte and IS were acceptable, and the analyte was stable during the assay and storage in plasma samples. The validated UPLC-MS/MS method was successfully applied to a drug-drug interaction study between gilteritinib and CYP3A4 inhibitors (fluconazole and itraconazole) in rats. Itraconazole significantly increased the exposure of gilteritinib, and affected the pharmacokinetics of gilteritinib in rats, not fluconazole. CONCLUSION: A further clinical study should be conducted to investigate the effect of itraconazole on the metabolism of gilteritinib in subjects.

Simultaneous Determination of Rivaroxaban and Enalapril in Rat Plasma by UPLC-MS/MS and Its Application to A Pharmacokinetic Interaction Study.

BACKGROUND AND OBJECTIVES: There have been no animal experiments and clinical studies on the pharmacokinetic interaction between rivaroxaban and enalapril. To investigate whether a potential pharmacokinetic interaction is present between rivaroxaban and enalapril, a rapid and sensitive Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine the concentration of rivaroxaban and enalapril in rat plasma and was then applied to a pharmacokinetic interaction study. METHODS: The analytes were separated on an Acquity UPLC BEH C18 chromatography column (2.1 × 50 mm, 1.7 µm) with acetonitrile and 0.1% formic acid as the mobile phase with gradient elution. The mass spectrometer was operated in multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of 436.1 → 145.1 m/z for rivaroxaban, 377.3 → 234.2 m/z for enalapril and 285.2 → 193.1 m/z for diazepam (IS). RESULTS: The method was validated over the concentration range of 1.0-200 ng/mL for rivaroxaban and 0.5-100 ng/mL for enalapril. The intra- and inter-day precision and accuracy of the quality control (QC) samples exhibited relative standard deviations (RSD) < 9.4% and the accuracy values ranged from - 8.3 to 9.6%. After co-administration of rivaroxaban and enalapril, the maximum plasma concentration (Cmax) and area under the systemic drug concentration-time curve from time 0 to infinity (AUC0-∞) of rivaroxaban were significantly increased by 19.6% (p < 0.05) and 21.3% (p < 0.05), respectively. On the contrary, the plasma clearance rate (CL/F) of rivaroxaban and enalapril was significantly decreased by 17.8% (p < 0.05) and 23.8% (p < 0.05), respectively. CONCLUSIONS: The UPLC-MS/MS method was successfully applied to simultaneous determination of rivaroxaban and enalapril in rat plasma and applied to study the pharmacokinetic interaction between rivaroxaban and enalapril. The co-administration of rivaroxaban and enalapril resulted in a significant drug interaction in rats.