Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both

Background:Transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) plays a key role in detoxification of electrophiles via formation of glutathione (GSH) adducts and subsequent excretion into extracellular spaces. We found that reactive sulfur species (RSS), such as cysteine persulfides produced by cystathionine γ-lyase (CSE), capture environmental electrophiles through formation of sulfur adducts. However, contributions of Nrf2 and CSE to the blockage of environmental electrophile-mediated toxicity remain to be evaluated.Objectives:The aim of this study was to clarify roles that CSE and Nrf2 play in the protection against various environmental electrophiles. We also wished to clarify the molecular basis of the developmental window of toxicity through investigating expression levels of Nrf2, RSS-producing enzymes, and sulfur nucleophiles during developmental stages of mice.Methods:Wild-type (WT), CSE knockout (KO), Nrf2 KO, Nrf2/CSE double KO (DKO) mice, and their primary hepatocytes were analyzed in this study. Cadmium (Cd), methylmercury (MeHg), 1,4-naphthoquinone, crotonaldehyde, and acrylamide were used. We conducted Western blotting, real-time polymerase chain reaction (PCR), 3-(4,5-dimethylthiazol-2-yl)-2,5-triphenyl tetrazolium bromide (MTT) assays, liquid chromatography–electrospray ionization–tandem mass spectrometry (LC-ESI-MS/MS) analysis, alanine transaminase (ALT) activity, histopathological analysis, and rotarod test.Results:Primary hepatocytes from DKO mice were significantly more sensitive to the environmental electrophiles than each single KO counterpart. Both Nrf2 and CSE single KO mice were highly susceptible to Cd and MeHg, and such sensitivity was further exacerbated in the DKO mice. Lower-level expressions of CSE and sulfur nucleophiles than those in adult mice were observed in a window of developmental stage.Conclusions:Our mouse model provided new insights into the response to environmental electrophiles; while Nrf2 is recognized as a key transcription factor for detoxification of environmental electrophiles, CSE is crucial factor to repress their toxicity in a parallel mode. In addition, the sensitivity of fetuses to MeHg appears to be, at least in part, associated with the restricted production of RSS due to low-level expression of CSE. https://doi.org/10.1289/EHP494

Hypergastrinemia and a duodenal ulcer caused by gastric duplication

BackgroundHypergastrinemia and the resultant peptic ulcer related to an enteric duplication has been quite rarely reported in the literature.Case presentationWe herein report the case of a 4-year-old girl who presented with hypergastrinemia and a duodenal ulcer at 2 years of age. She had been followed up with a proton pump inhibitor, which resulted in resolution of the ulcer; however, unexplained hypergastrinemia had continued. A cystic lesion at the antrum was discovered at 4 years of age, which we suspected to be a gastric duplication. After we resected the lesion, the hypergastrinemia resolved without recurrence of the duodenal ulcer. The histology was compatible with a gastric duplication, and the lumen was lined with antral mucosa that strongly stained positive for gastrin. We presumed that the antral mucosa inside the duplication in our case had no hydrogen ion feedback inhibition of gastrin release from gastrin cells and increased release of gastrin from the mucosa inside the duplication led to the duodenal ulcer. Only two cases have been reported in the literature that had hypergastrinemia related to enteric duplication.ConclusionGastric duplication should be included in the differential diagnosis of sustained hypergastrinemia in children

A novel technique for securing tracheal blood supply in salvage anterior mediastinal tracheostomy

Introduction: The only way for complete cure of advanced esophageal cancer with invasion to the mid-trachea is anterior mediastinal tracheostomy (AMT), which has a significantly high risk of fatal complications. The shorter tracheal stump is beneficial for good blood supply, but complicates to create a tracheostomy. Presentation of case: A 71-year-old patient with a history of advanced cervical esophageal cancer who was treated with definitive chemoradiotherapy 3 years earlier had local recurrence on the left side of the trachea despite salvage lymphadenectomy for solitary left paratracheal lymph node recurrence 1 year earlier. AMT involving a resection of nearly the whole trachea was needded for complete resection. However, the recurrenced tumor was localized on the tracheal left side. We designed the new surgical procedure to preserve a longer segment of the unaffected right tracheal wall by diagonal cut (3.6 cm longer than on the left side) while maintaining adequate blood flow by preserving the right lateral vascular pedicle in a state of connecting with the right lobe of the thyroid gland and the right tracheal stump. The postoperative course was uneventful, and at 1 year postoperatively, no tumor recurrence has been detected. Discussion: Preservation of the lateral vascular pedicle enables a longer tracheal stump by securing sufficient blood supply and a longer tracheal stump in AMT, even when unilateral, enables to create tracheostomy more surely, preventing fatal complications. Conclusion: This novel procedure should be considered in cases with tumor invasion extending into the lower mid-trachea that is limited to one side