Alternative plasticizers induced immunotoxicity in THP-1 macrophages via mitochondrial dysfunction-driven metabolic reprogramming

As emerging contaminants, alternative plasticizers (APs) are increasingly prevalent in the environment due to their use as replacements for regulated phthalates, yet their potential health risks, particularly immunotoxicity, remain poorly understood. To address this critical gap, we systematically evaluated seven environmentally pervasive and toxicologically concerning APs(ASE, ATBC, TOTM, DEHT, DEHA, DINCH, ESBO) alongside DEHP. We adopted a comprehensive multi-modal strategy to reveal the unique immunotoxic effects of each compound and their underlying mechanisms. Our findings demonstrate that APs differentially disrupt macrophage immune functions: ASE and DEHA enhanced adhesion/phagocytosis, whereas ATBC, TOTM, DEHT, DINCH, and ESBO significantly suppressed these capacities. Mitochondrial profiling revealed that ASE, ATBC, and TOTM increased mitochondrial mass, while DEHT, DEHA, DINCH, and ESBO reduced it. Notably, ASE, DEHT, and ESBO induced mitochondrial dysfunction, characterized by diminished membrane potential (MMP) and elevated mitochondrial reactive oxygen species (mtROS), implicating mitochondrial impairment as a key mechanism of APs-induced immunotoxicity. Analysis of 92 immune-related proteins further indicated a shift toward pro-inflammatory polarization. Metabolomics analysis further linked immunotoxicity to metabolic reprogramming, revealing associated metabolic disturbances. Collectively, this study provides a systematic dissection of APs-immunotoxic mechanisms through a mitochondria-metabolism-immune axis. Our findings offer crucial evidence for the informed safety assessment and regulatory prioritization of these ubiquitous environmental plasticizers.