The teleost inflammasome as a biosensor in developmental toxicology

Abstract

Standard environmental risk assessment frameworks, such as the OECD 236 Fish Embryo Acute Toxicity (FET) test, rely heavily on macroscopic morphological endpoints that may fail to detect subtle, sublethal molecular disruptions before phenotypic damage becomes apparent. Mechanism-based biomarkers capable of ultra-early toxicity prediction are therefore needed. The teleost inflammasome, particularly the interleukin-1 beta (IL-1β) and gasdermin (GSDM) execution pathway, represents a promising high-resolution molecular biosensor for developmental toxicity screening. A systematic review was conducted to evaluate evidence on the teleost inflammasome and the IL-1β/GSDM pathway in response to biological and abiotic stressors, with particular emphasis on their potential application as mechanism-based biomarkers of developmental toxicity. Available evidence indicates that IL-1β signaling, traditionally characterized as an antimicrobial defense mechanism, can also respond to cellular stress induced by abiotic stressors, including heavy metals, pesticides, and persistent organic pollutants. Sublethal xenobiotic exposure can induce oxidative stress and reactive oxygen species overproduction, leading to the release of damage-associated molecular patterns (DAMPs) and activation of the canonical NLRP3/ASC/caspase-1 platform. Following teleost-specific whole-genome duplication, gasdermin paralogs expanded into distinct variants, including GSDMEa, GSDMEb, and GSDMEc. N-terminal proteolytic cleavage of GSDMEa and GSDMEb generates GSDMEa-N and GSDMEb-N fragments that can mediate pyroptotic pore formation and IL-1β release. However, existing ecotoxicological studies rely predominantly on transcriptional (mRNA) data and rarely verify functional gasdermin protein cleavage. The available evidence supports the IL-1β/GSDM axis as a potentially sensitive molecular indicator of cellular stress and developmental toxicity in teleosts. Transitioning from descriptive morphological assessment toward functional proteomic profiling of GSDMEa/b cleavage, particularly in Danio rerio embryos, may provide an additional mechanistic window for complementing emerging mechanism-based approaches and potentially improving the sensitivity and resolution of developmental toxicity assessment.