NLRP3 inflammasome dysregulation by endocrine-disrupting chemicals and heavy metals: Developmental programming, sex differences, and inflammaging across the lifespan

Environmental exposure to heavy metals and endocrine-disrupting chemicals (EDCs) activates the NLRP3 inflammasome, driving chronic inflammation that worsens or may underlie cardiovascular disease, neurodegeneration, and accelerated aging. This review examines the molecular mechanisms by which lead, cadmium, mercury, arsenic, bisphenol A, phthalates, and dioxins modulate NLRP3 signaling. Lead and cadmium activate NLRP3 through mitochondrial dysfunction and oxidative stress, whereas mercury and arsenic suppress inflammasome assembly by preventing apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization. EDCs engage receptor-mediated pathways: aryl hydrocarbon receptor (AhR) activation directly represses NLRP3 transcription, yet bisphenol A and phthalates override this suppression through NF-κB activation. Developmental timing critically determines outcomes such as prenatal exposures epigenetically programing persistent NLRP3 dysregulation. Sex hormones have been shown to modulate distinct inflammatory landscapes: estrogen suppresses NLRP3 via ERβ-dependent mechanisms, while testosterone amplifies inflammasome-dependent pathology. The skin serves as a primary interface for environmental chemical exposure and cutaneous NLRP3 activation. NLRP3-deficient mice exhibit 34% increased lifespan, and pharmacological inhibition with MCC950 extends lifespan in progeria models. The CANTOS trial demonstrated that targeting inflammation through IL-1β neutralization confers cardiovascular benefits in high-risk humans. These findings position NLRP3 as a central integrator through which the chemical exposome accelerates inflammaging and identify inflammasome inhibition as a therapeutic strategy for environmental disease prevention.