Organ-specific apoptotic pathways induced by micro- and nanoplastics: a systematic review of in vitro toxicological evidence

The widespread presence of micro- and nanoplastics (MNPs) in environmental matrices and consumer products has raised increasing concern about their potential effects on human health. Due to their small size, persistence, and heterogeneous physicochemical properties, MNPs may interact with biological barriers, reach different cellular compartments, and trigger organ-specific toxic responses. Among the cellular events involved, apoptosis has emerged as a recurrent mechanism linking MNP exposure to tissue injury and functional impairment. This systematic review aimed to synthesize the available in vitro evidence on apoptosis-related toxicity induced by MNPs across different cell models and organoids, with particular attention to organ-specific patterns and underlying molecular pathways. Following a PECOS-based strategy and PRISMA guidance, a literature search was conducted in PubMed, Scopus, and Web of Science on 6 September 2024. Studies were screened using Rayyan, and 80 studies were included in the qualitative synthesis. Overall, the evidence indicates that MNP exposure induces cytotoxic effects in a wide range of cellular models representing the gastrointestinal tract, liver, lung, kidney, reproductive system, placenta, brain, cardiovascular system, skin, and blood-related compartments. Across these models, recurrent mechanisms included oxidative stress, mitochondrial dysfunction, loss of mitochondrial membrane potential, endoplasmic reticulum stress, calcium imbalance, activation of MAPK and PI3K/AKT-related signaling, dysregulation of Bcl-2 family proteins, caspase activation, and crosstalk with inflammatory, autophagic, and ferroptotic pathways. Particle size, surface chemistry, concentration, exposure time, and co-exposure with other contaminants influenced the magnitude and pattern of toxic responses. In conclusion, apoptosis represents a central mechanistic node in the organ-specific toxicity of MNPs in vitro . However, the translational relevance of current evidence remains limited by heterogeneity in particle characteristics, exposure conditions, and experimental models. Future studies should prioritize standardized protocols, environmentally relevant exposure scenarios, and advanced human-based models to better define the implications of MNP exposure for human health.