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

Abstract

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.

Keywords: chemical mixtures; cohort studies; endocrine-disrupting chemicals; hormone receptors; immune function; immunotoxicity; mouse models; organoid models; reproductive outcomes.

Graphical Abstract

Figure 1

A schematic representation of the impact of EDCs on the immune system. EDCs have complex and heterogeneous structures and can interact with hormone receptors in immune cells. This interaction may result in the activation, blockade, or modulation of the receptor function, altering signaling cascades and ultimately the cell phenotype. EDC-induced immunomodulation encompasses changes in surface protein expression, cytokine profile secretion, and cytotoxic activity. These phenotypic changes are not limited to individual immune cells but can translate to cell-to-cell interactions; for instance, the differentiation of dendritic cells toward a pro-inflammatory or tolerogenic subset will determine the cell fate of CD4⁺ T cells. Therefore, EDCs can potentially disrupt the immune system regulatory network, contributing to the development of allergies, autoimmune diseases, and reproductive outcomes (created with BioRender.com).

Figure 2

Concept, approach, and methodologies of ENDOMIX. The ENDOMIX consortium will assess the adverse health effects of real-life EDCs grounded on immunotoxicity as a central mechanism. Human populations are in constant contact with consumer products containing EDC mixtures, which can alter development, growth, and metabolism by targeting the endocrine, immune, and reproductive systems. This project will cover the complete chain of causality, from exposure to disease onset, by validating adverse effects of EDC mixtures of concern in European cohorts during windows of susceptibility (e.g., pregnancy and childhood). Subsequently, the impact of these EDC mixtures on the phenotype and function of immune and target cells will be characterized by using in vitro bioassays, barrier and organoid systems, and animal models. Newly-generated data and information available in databases will be employed to feed machine learning algorithms and develop roadmaps for EDC risk assessment (created with BioRender.com).