O-034 Gaining insight into the chemical exposome of deep endometriosis using metabolomics

Study question Do environmental chemicals play a role on deep endometriosis through metabolic disruption? Summary answer The present study support that women with deep endometriosis exhibit a specific metabolic profile associated to the internal exposure of persistent organic pollutants. What is known already A growing list of pollutants seems to be able to interact with and metabolic signaling pathways involved in the onset and progression of endometriosis. Up to date, most of research on environmental pollutants have focused on endocrine disrupting mechanisms, whereas their involvement on the metabolic shift observed on endometriosis lesions have not been studied yet. Persistent organic pollutants (POPs) such as organochlorine pesticides (OCPs) or per-/polyfluorinated substances (PFAS), have shown the capacity to alter the normal metabolic function through different mechanisms, including mitochondrial dysfunction or energy homeostatic imbalance. Previous metabolomic studies have failed to identify robust predictive biomarkers of endometriosis. Study design, size, duration We conducted an observational metabolomic-wide case-control study with French women undergoing surgery for endometriosis or In vitro fertilization, with and without surgically confirmed endometriosis (n = 137). A “meet-in-the-middle” systematic review of observational and experimental studies was conducted to identify metabolic pathways overlapping POPs and endometriosis in order to support the biological plausibility. Participants/materials, setting, methods Women’s serum was analyzed using gas and liquid chromatography coupled to high-resolution mass spectrometry (HRMS) to measure the levels of 14 polychlorinated biphenyls (PCB), six OCPs and six PFAS. A comprehensive targeted metabolomic profiling was conducted using HRMS and 1H nuclear magnetic resonance (1H NMR). An ultra-targeted study including inflammatory mediators oxylipins and twenty-six free fatty acids was conducted by liquid and gas chromatography coupled to tandem mass spectrometry, respectively. Main results and the role of chance The PCB180, PCB167 and the pesticide trans-nonachlor were associated with a higher risk of deep endometriosis. Women with endometriosis exhibited a distinctive metabolic profile, with elevated serum levels of lactate, ketone bodies and multiple amino acids and lower levels of bile acids, phosphatidylcholines (PCs), cortisol and hippuric acid. The pesticide c was positively associated with deep endometriosis risk and the alteration of 2-hydroxybutyrate pathway. In turn, negative associations were found between the fluorinated industrial pollutant, perfluoroundecanoic acid (PFUnA) and levels of prostaglandin E2, 15-hydroxyeicosatetraenoic acid (15HETE) and 5-HETE. Levels of 5-HETE and 8,9-epoxyeicosatrienoic acid were found to be at lower levels in women with endometriosis-related infertility. Limitations, reasons for caution This study has a limited sample size, and the cross-sectional design does not prevent the reverse causation. The results may not be generalized to mild or superficial forms of endometriosis and general population. Further observational and experimental studies will be required to confirm these findings. Wider implications of the findings The present study showed that women with deep endometriosis had higher levels of POPs compared to women with benign conditions. A targeted high-throughput metabolomic analysis allowed gaining insight into metabolic pathways potentially linking the pesticide trans-nonachlor with endometriosis. Trial registration number No