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Antenatal Exposure to Plastic Pollutants: Study of the Bisphenols and Perfluoroalkyls Effects on Human Stem Cell Models
Gaggi Giulia, Di Credico Andrea, Barbagallo, Federica Ballerini Patrizia, Ghinassi Barbara
Endocrine disruptors (EDs), such as Bisphenols (BPs) and Perfluoroalkyls (PFs), are a class of plastic pollutants widely used in industrial applications. Human exposure to these molecules usually occurs through ingestion of contaminated food and water. Once entered the human body they can interfere with endogenous hormone signaling, leading to a wide spectrum of diseases. It has been reported that BPs and PFs can cross the placental barrier accumulating in the fetal serum, but the detrimental consequences for human development remain to be clarified. Here we analyze the effects of different doses of bisphenol A and S (BPA, BPS) perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) on proliferation and mitochondrial health on different types of stem cells: through an integrated approach that combines data from pluripotent stem cells (hiPSCs) with that from the “environment” in which the embryo develops (fetal annexes-derived perinatal stem cells) we verified the potential developmental toxicity of the in utero EDs exposure. Data obtained showed that overall, BPs, and PFs tended to increase the proliferation rate of perinatal stem cells; a similar response was observed in hiPSCs exposed to very low doses of BPs and PFs, while at higher concentrations these chemicals were toxic; in addition, both the BPs and the PFs exerted a mitotoxic effects hiPSCs at all the concentration studied. All these data suggest that antenatal exposure to BPs and PFs, also at very low concentrations, may modify the biological characteristics of stem cells present in both the developing fetus and the fetal annexes, thus perturbing normal human development.
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Machine learning identifies phenotypic profile alterations of human dopaminergic neurons exposed to bisphenols and perfluoroalkyls
Di Credico Andrea, Weiss Amélie, Corsini Massimo, Gaggi Giulia, Ghinassi Barbara
Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by the loss of midbrain dopaminergic neurons. Endocrine disrupting chemicals (EDCs) are active substances that interfere with hormonal signaling. Among EDCs, bisphenols (BPs) and perfluoroalkyls (PFs) are chemicals leached from plastics and other household products, and humans are unavoidably exposed to these xenobiotics. 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. Previous studies demonstrated that machine learning (ML) applied to microscopy data can classify different cell phenotypes based on image 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. Cells exposed for 72 h to the xenobiotics were stained with neuronal markers and evaluated using high content microscopy yielding 126 different phenotypic features. Three different ML models (LDA, XGBoost and LightGBM) were trained to classify EDC-treated versus control mDANs. EDC treated mDANs were identified with high accuracies (0.88–0.96). 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. Moreover, microtubule-associated protein 2 (MAP2) neurite length and branching were significantly diminished in treated neurons. Our study shows that human mDANs are adversely impacted by exposure to EDCs, causing their phenotype to shift and exhibit more characteristics of PD. 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.
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Bisphenols and perfluoroalkyls alter human stem cells integrity: A possible link with infertility
Gaggi Giulia, Di Credico Andrea, Barbagallo Federica, Ghinassi Barbara, Di Baldassarre Angela
Abstract: Bisphenols and Perfluoroalkyls are chemical compounds widely used in industry known to be endocrine disruptors (EDs). Once ingested through contaminated aliments, they mimic the activity of endogenous hormones leading to a broad spectrum of diseases. Due to the extensive use of plastic in human life, particular attention should be paid to antenatal exposure to Bisphenols and Perfluoroalkyls since they cross the placental barrier and accumulates in developing embryo. Here we investigated the effects of Bisphenol-A (BPA), Bisphenol-S (BPS), perfluorooctane-sulfonate (PFOS) and perfluorooctanoic-acid (PFOA), alone or combined, on human-induced pluripotent stem cells (hiPSCs) that share several biological features with the stem cells of blastocysts. Our data show that these EDs affect hiPSC inducing a great mitotoxicity and dramatic changes in genes involved in the maintenance of pluripotency, germline specification, and epigenetic regulation. We also evidenced that these chemicals, when combined, may have additive, synergistic but also negative effects. All these data suggest that antenatal exposure to these EDs may affect the integrity of stem cells in the developing embryos, interfering with critical stages of early human development that might be determinant for fertility. The observation that the effects of exposure to a combination of these chemicals are not easily foreseeable further highlights the need for wider awareness of the complexity of the EDs effects on human health and of the social and economic burden attributable to these compounds.
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The Effects of Combined Exposure to Bisphenols and Perfluoroalkyls on Human Perinatal Stem Cells and the Potential Implications for Health Outcomes
Di Credico, A., Gaggi, G., Bucci, I., Ghinassi, B., Di Baldassarre, A.
Abstract: The present study investigates the impact of two endocrine disruptors, namely Bisphenols (BPs) and Perfluoroalkyls (PFs), on human stem cells. These chemicals leach from plastic, and when ingested through contaminated food and water, they interfere with endogenous hormone signaling, causing various diseases. While the ability of BPs and PFs to cross the placental barrier and accumulate in fetal serum has been documented, the exact consequences for human development require further elucidation. The present research work explored the effects of combined exposure to BPs (BPA or BPS) and PFs (PFOS and PFOA) on human placenta (fetal membrane mesenchymal stromal cells, hFM-MSCs) and amniotic fluid (hAFSCs)-derived stem cells. The effects of the xenobiotics were assessed by analyzing cell proliferation, mitochondrial functionality, and the expression of genes involved in pluripotency and epigenetic regulation, which are crucial for early human development. Our findings demonstrate that antenatal exposure to BPs and/or PFs may alter the biological characteristics of perinatal stem cells and fetal epigenome, with potential implications for health outcomes at birth and in adulthood. Further research is necessary to comprehend the full extent of these effects and their long-term consequences.