![]() These findings underscore the ability of EDCs to enter and persist within the human body, raising serious concerns about their detrimental effects on human health. EDCs have been detected in human serum, urine, placental tissue, umbilical cord blood and breast milk 9, 10, 11. As a consequence, humans are constantly and unavoidably exposed to these xenobiotics that may threaten human health via different routes such as dermal absorption, inhalation and dietary ingestion 8. Similarly, PFs are found in different items of common use as cookware and paper food packaging 7. These chemicals are widely diffuse, since BPs are used to produce polymers and resins for the production of polycarbonate plastics, food packaging, food cans, and thermal receipts 6. EDCs include bisphenols (BPs), such as bisphenol A (BPA) and S (BPS), and perfluoroalkyls (PFs), such as perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA). These features lead to the onset of the characteristic motor (e.g., bradykinesia, rigidity, and tremors) and non-motor (e.g., cognitive impairment, psychiatric disturbances, and sleep disorders) symptoms of PD 4.Įndocrine disrupting chemicals (EDCs) are hormonally active substances present in the environment, including household and industrial products, and can have adverse effects on human health 5. Importantly, αSyn aggregates can disrupt normal cellular processes and contribute to the repression of tyrosine hydroxylase (TH), the rate-limiting enzyme in brain catecholamine biosynthesis, decreasing dopamine production 3. The main cellular and molecular hallmarks of PD are represented by the loss of midbrain dopaminergic neurons (mDANs) in the substantia nigra pars compacta, and intracellular aggregation of alpha-synuclein (αSyn), respectively 2. The pathogenesis of PD involves a combination of environmental and genetic risk factors, which collectively contribute to the development and progression of the disease. Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting about 3% of the population above 65 years 1. Importantly, ML-supported high-content imaging can identify concrete but subtle subcellular phenotypic changes that can be easily overlooked by visual inspection alone and that define EDCs effects in mDANs, thus enabling further pathological characterization in the future. Our study shows that human mDANs are adversely impacted by exposure to EDCs, causing their phenotype to shift and exhibit more characteristics of PD. Moreover, microtubule-associated protein 2 (MAP2) neurite length and branching were significantly diminished in treated neurons. Assessment of the phenotypic feature contribution to the classification showed that EDCs induced a significant increase of alpha-synuclein (αSyn) and tyrosine hydroxylase (TH) staining intensity within the neurons. EDC treated mDANs were identified with high accuracies (0.88–0.96). Three different ML models (LDA, XGBoost and LightGBM) were trained to classify EDC-treated versus control mDANs. Cells exposed for 72 h to the xenobiotics were stained with neuronal markers and evaluated using high content microscopy yielding 126 different phenotypic features. In this study, the effect of BPs and PFs at different concentrations within the real-life exposure range (0.01, 0.1, 1, and 2 µM) on the phenotypic profile of human stem cell-derived midbrain dopaminergic neurons (mDANs) was analyzed. Previous studies demonstrated that machine learning (ML) applied to microscopy data can classify different cell phenotypes based on image features. Data from animal studies suggest that EDCs exposure may play a role in PD, but data about the effect of BPs and PFs on human models of the nervous system are lacking. ![]() ![]() Among EDCs, bisphenols (BPs) and perfluoroalkyls (PFs) are chemicals leached from plastics and other household products, and humans are unavoidably exposed to these xenobiotics. Endocrine disrupting chemicals (EDCs) are active substances that interfere with hormonal signaling. Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by the loss of midbrain dopaminergic neurons.
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