Rationale and study protocol of the MAMELI Cohort study (Mapping the Methylation of repetitive elements to track the Exposome effects on health: the city of Legnano as a Living lab).

The concept of the exposome encompasses all the factors influencing human health throughout the life course. The exposome induces epigenetic changes, such as DNA methylation, which influence gene expression and impact overall health. Several recent studies have explored how repetitive elements (REs) in the genome can be activated in response to environmental stimuli. However, most of these investigations have assumed that altered RE methylation is always detrimental to individual health. The MAMELI project proposes an alternative hypothesis: that some REs are plastic entities capable of responding physiologically to environmental stimuli without compromising genome stability. This hypothesis suggests that the ability of DNA to adapt to environmental triggers could be monitored and used as an indicator of health resilience. To test this hypothesis, the MAMELI project will enroll 6,200 participants from the city of Legnano (Italy) and will be conducted in three main phases: i) A total of 200 healthy participants will undergo DNA methylation analysis through third-generation sequencing at two time points: T0 (baseline) and T1 (6 months after T0). This phase aims to identify a set of REs ("differential REs") whose methylation changes in response to the exposome without affecting genome stability; ii) This phase will include 2,700 subjects (the original 200 participants from the discovery phase plus 2,500 additional subjects). The goal will be to develop a predictive algorithm (the MAMELI algorithm) that links the exposome to RE methylation status, creating a "RE methylation signature" reflecting the environmental impact on DNA methylation; iii) In this phase, the MAMELI algorithm will be applied to a separate cohort of 3,500 participants to compare the measured RE methylation signature with values predicted by the algorithm. Additionally, an intervention study will be embedded within the cohort to assess the reversibility of RE methylation following lifestyle changes. The MAMELI project offers a novel perspective in the field of epigenetics and environmental health, demonstrating how the epigenome can act as a sensor for environmental changes and how this interaction can be harnessed for disease prevention. If validated, the MAMELI algorithm could become a powerful tool for identifying individuals at risk and developing personalized interventions to improve global health outcomes.