Exposure factors may trigger epigenetic changes, notably in DNA methylation of repetitive elements (REs). For instance, LINE-1 elements typically methylated in normal cells, can become active in response to environmental cues. Prior research has predominantly assumed that all epigenetic changes are detrimental, but we suggest a novel perspective: some environmentally-induced changes could be physiological responses facilitating individual adaptation.

In 185 subjects with a Body Mass Index >25, we evaluated through regression models the association between 1-week exposure to particulate matter ≤ 10 µm (PM10) and LINE-1 methylation (assessed by Pyrosequencing). We used the estimated regression function to predict values for each study subject and we calculated the relative percent difference (PD) between the measured (i.e., observed) LINE-1 methylation and the predicted (i.e., expected) from the model. We hypothesize that the greater the difference between the observed and the expected, the greater the inability of the subject to adapt to external stimuli.

We observed a negative association between PM10 and LINE-1 methylation (β = -0.038; 95% CI -0.052; -0.0233; p-value <0.0001), in agreement with previous evidence. Applying the new approach that we are proposing, we calculated the PD between the measured LINE-1 methylation values and the estimates predicted from the model and we identified subjects showing a negative PD (i.e., observed values lower than estimated ones) higher than 5%. The health status of these subjects was associated with a 4-fold greater risk of metabolic syndrome when compared to all other subjects (Odds Ratio [OR] = 3.78; 95% CI 1.28-11.20; p-value 0.016) and a 9-fold higher risk of hypertension (OR = 8.97; 95% CI 1.15-69.82; p-value 0.036).

The proposed approach will be extended (for example considering a wide range of environmental exposures and lifestyle factors) and thoroughly tested in a population of more than 6,000 subjects in the MAMELI project (“MApping the Methylation of repetitive elements to track the Exposome effects on health: the city of Legnano as a LIving lab”) which is about to start and has been funded by the European Research Council (project code: ERC-2022-COG-101086988). If confirmed, our hypothesis will pave the way to support the notion that REs are fundamental components for monitoring individual adaptability to environmental stimuli.