The ENDOMIX perspective: how everyday chemical mixtures impact human health and reproduction by targeting the immune system†.

Endocrine-disrupting chemicals are natural and synthetic compounds found ubiquitously in the environment that interfere with the hormonal-immune axis, potentially impacting human health and reproduction. Exposure to endocrine-disrupting chemicals has been associated with numerous health risks, such as neurodevelopmental disorders, metabolic syndrome, thyroid dysfunction, infertility, and cancers. Nevertheless, the current approach to establishing causality between these substances and disease outcomes has limitations. Epidemiological and experimental research on endocrine-disrupting chemicals faces challenges in accurately assessing chemical exposure and interpreting non-monotonic dose response curves. In addition, most studies have focused on single chemicals or simple mixtures, overlooking complex real-life exposures and mechanistic insights, in particular regarding endocrine-disrupting chemicals' impact on the immune system. The ENDOMIX project, funded by the EU's Horizon Health Program, addresses these challenges by integrating epidemiological, risk assessment, and immunotoxicology methodologies. This systemic approach comprises the triangulation of human cohort, in vitro, and in vivo data to determine the combined effects of chemical mixtures. The present review presents and discusses current literature regarding human reproduction in the context of immunotolerance and chemical disruption mode of action. It further underscores the ENDOMIX perspective to elucidate the impact of endocrine-disrupting chemicals on immune-reproductive health.