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Toxicogenomic differentiation of functional responses to fipronil and imidacloprid in Daphnia magna
(2021)
Active substances of pesticides, biocides or pharmaceuticals can induce adverse side effects in the aquatic ecosystem, necessitating environmental hazard and risk assessment prior to substance registration. The freshwater crustacean Daphnia magna is a model organism for acute and chronic toxicity assessment representing aquatic invertebrates. However, standardized tests involving daphnia are restricted to the endpoints immobility and reproduction and thus provide only limited insights into the underlying modes-of-action. Here, we applied transcriptome profiling to a modified D. magna Acute Immobilization test to analyze and compare gene expression profiles induced by the GABA-gated chloride channel blocker fipronil and the nicotinic acetylcholine receptor (nAChR) agonist imidacloprid. Daphnids were expose to two low effect concentrations of each substance followed by RNA sequencing and functional classification of affected gene ontologies and pathways. For both insecticides, we observed a concentration-dependent increase in the number of differentially expressed genes, whose expression changes were highly significantly positively correlated when comparing both test concentrations. These gene expression fingerprints showed virtually no overlap between the test substances and they related well to previous data of diazepam and carbaryl, two substances targeting similar molecular key events. While, based on our results, fipronil predominantly interfered with molecular functions involved in ATPase-coupled transmembrane transport and transcription regulation, imidacloprid primarily affected oxidase and oxidoreductase activity. These findings provide evidence that systems biology approaches can be utilized to identify and differentiate modes-of-action of chemical stressors in D. magna as an invertebrate aquatic non-target organism. The mechanistic knowledge extracted from such data will in future contribute to the development of Adverse Outcome Pathways (AOPs) for read-across and prediction of population effects.
Background: Neurotoxic envenomation following bites by kraits (Bungarus species) is a leading cause of snakebite mortality in South Asia. Over a long time, this had been attributed only to one species, the common krait (Bungarus caeruleus). However, recent research has provided increasing evidence of the involvement of several krait species. Here, we report a fatal case of neurotoxic envenomation following the bite of a greater black krait (Bungarus niger) in Nepal.
Case presentation: A 33-year-old man was bitten in the outdoor corridor of his home in the eastern hills of Ilam district while handling a snake he thought to be non-venomous. He subsequently developed severe abdominal pain, frequent vomiting, and signs of neurotoxic envenomation leading to respiratory paralysis. The patient did not respond to Indian polyvalent antivenom given 4 h after the bite and died under treatment 8 h after the bite. This is the second time that a B. niger was observed in Nepal, the first documented case of envenomation by this species in the country and the sixth reported case worldwide.
Conclusions: Previous distribution records – from eastern India and western Nepal, from western hills in Nepal, and from lowland localities in India and Bangladesh – indicate risk of envenomation by B. niger throughout the low and intermediate elevations of Nepal up to at least 1,500 m above sea level. As very few people in Nepal bring killed snakes to healthcare centers and because there is a general belief among local people that there are no kraits in the hills, bites by B. niger are likely to be misdiagnosed and underreported.
Cancer therapies have experienced significant advances in recent years. While conventional cytotoxic chemotherapy has long been the cornerstone for the treatment of many tumor entities, uprising immunotherapies have revolutionized the therapeutic landscape. Among them, immune checkpoint inhibitors (ICIs) with their demonstrated increased overall survival rates and response rates in cancer patients are now FDA-approved for metastatic melanoma and multiple other malignancies. Despite their clinical benefit in cancer therapies, ICIs can induce unique autoimmune-like toxicities known as immune-related adverse events (irAEs), which can involve any organ system including the nervous system. Although neurotoxicities are rare complications of ICI therapy they are often severe and can lead to long-term disability or even death if left untreated.
Neurological irAEs exhibit a broad spectrum of clinical presentations affecting the entire nervous system. Diagnosing neurological irAEs is often challenging as symptoms and laboratory findings can be uncharacteristic for common neurological disorders and clinical experience with ICI-mediated toxicities is still limited. In light of expanding clinical indications for ICIs, physicians will encounter ICI-mediated neurotoxicities more frequently. Thus, thorough characterizations of the diverse set of neurological irAEs are essential for optimal patient care, the prevention of severe ICI-mediated complications, and the development of diagnostic and therapeutic algorithms. This work portrays the clinical presentation, management and outcome of neurological irAEs following ICI therapies.
Patients with neurotoxicities related to ICIs who presented at the Yale New Haven Hospital between January 2014 and June 2018 were retrospectively identified from the quality control database. A comprehensive chart review was performed and data regarding patient demographics, medical history, ICI regimen and neurotoxicity were recorded. In total, 18 patients with neurological irAEs following ICI therapy for melanoma, small cell lung cancer, non-small cell lung cancer, and Merkel-cell carcinoma were identified. Neurotoxicities included central nervous system disorders comprising central demyelinating disorder,autoimmune encephalitis predominantly affecting the grey matter, and aseptic meningitis. Peripheral nervous system toxicities included sensorimotor polyneuropathy and myasthenia gravis. Cases of hypophysitis were also recorded. Time to onset of neurological irAEs ranged from 1 to72 weeks with a median of five weeks. In all patients ICIs were held and steroids initiated. Additional immunomodulatory therapies were required in nine patients. Sixteen of 18 patients showed neurological improvement. Fourteen patients had highgrade neurotoxicity (grade 3-4), six of whom deceased due to cancer progression, while none of the low-grade neurotoxicity patients (grade 1-2) died. High-grade neurotoxicity was identified as a negative prognostic marker for overall survival (p = 0.046).
This work shows that neurotoxicities present early-onset, rapidly progressive complications of ICIs with a broad spectrum of clinical phenotypes affecting the central nervous system, peripheral nervous system, and neuroendocrine system. A high index of caution for neurological irAEs is warranted throughout ICI therapy as timely diagnosis and management can reduce morbidity and mortality. Randomized clinical trials are needed to develop standardized diagnostic and therapeutic algorithms of ICI-induced neurotoxicities.