Nanoparticle-specific effects on developmental processes and the role of mitochondria: an in vitro study

environmental sources. The aim of this work was to determine simultaneously levels of Al, As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Se and Zn in by ICP-MS in maternal and cord blood samples obtained at delivery in a cohort from the population of Sevilla (Spain) and to stablish potential relationships between these metals an metalloids and newborn's parameters at birth, pregnancy details and the epidemiologic information obtained using an extensive questionnaire data. Results showed a positive correlation between maternal and cord blood for all metals except for Cr and Cu. The strongest correlation was found for Hg (r = 0.779, p < 0.005). Positive but weaker correlations between maternal blood and lifestyle habits were also found, such as As and weekly rice consumption or Hg and Cd and fish consumption. Metals, such as calcium (Ca), zinc (Zn), and copper (Cu) in the gestational stage are essential to proper organ and system formation due to their participation in structural proteins and as part of metabolic and enzymatic processes. On the other hand, metals or metalloids, such as arsenic (As), mercury (Hg), lead (Pb), cadmium (Cd), and vanadium (V), among others, could be potentially toxic (PTMs) because they interfere with vital processes. There is a need to have biomarkers of exposure to essential and toxic metals during the uterine stage, and metal content in hair is a good marker to assess the exposure to metals that influence health and disease, representing the exposure of a prolonged period (months). The aim of this study was to evaluate the concentration of some PTMs and essential metals in hair samples of newborn-mother pairs, and test the metals transfering to fetuses during pregnancy. A cross-sectional pilot study was conducted on 96 newborns and their mothers who gave birth in a highly polluted area of the Mexican State in Central Mexico. Hair samples were collected from August to October 2015 and metal quantification was performed by inductively coupled plasma mass spectrometry (ICP-MS). A total of 11 elements were quantified. Maternal's hair samples had median PTM concentrations from 8 to 176 ppb in the following order: V >Pb >Hg >U >Sb >As >Cd, while the newborn's sample concentrations were lower, ranging from 1 to 76.5 ppb as follows: Hg >Sb >V >Pb >Cd >As >U. The results showed a strong positive correlation (Sperman) between the hair concentration of Hg in the mother and the newborn (r > 0.69), a moderate positive correlation in As, B, and Zn (r = 0.69-0.3) concentrations, and a weak positive correlation in those of Ca, Cu, and U (r ≤ 0.3); hair concentrations of Pb, Cd, Sb, or V showed no correlation in the mother-newborn pair. Our data showed that PTMs are transferred to the fetus during pregnancy, their concentrations in hair represent a good biomarker of prenatal exposure, although not all PTMs in newborns showed similar relationships with concentrations in their mothers, suggesting they have different toxicokinetics. References [1] Sakamoto M., Man Chan H., Domingo J. L., Kubota M., & Murata K. (2012). Changes in body burden of mercury, lead, arsenic, cadmium and selenium in infants during early lactation in comparison with placental transfer. Ecotoxicology and Environmental Safety, 84(1), 179-184. G. (2009). Use of scalp hair as indicator of human exposure to heavy metals in an electronic waste recycling area. Humans encounter nanoparticles (NPs) on a day-today basis. Potential hazards have been identified for several common NPs, but current risk assessment strategies are often insufficient. To enable proper hazard characterization, we need fundamental knowledge on how cellular location affects NP toxicity, and how this is related to the physicochemical properties of NPs. There is also a strong need for mechanistic data, especially with regard to developmental toxicity. The current study investigates the underlying mechanisms activated during particle-induced effects on cell cycle dynamics, in relation to the particle characteristics and kinetic profiles. We compared three widely occurring NPs, namely silver (PVP-Ag), Titanium dioxide (TiO 2) and Polystyrene (PS). In line with the 3R principles and REACH regulation, human dental pulp stem cells (hDPSCs) are used as a proxy for mesenchymal stem cells and developing tissues. The NPs were characterized with transmission electron microscopy (TEM) and dynamic light scattering. Based on TEM and confocal microscopy we showed uptake of all three NPs which mostly localize to vesicles. All viability and cell cycle experiments were performed up to 72 h of exposure. PVP-Ag NPs and TiO 2 NPs were cytotoxic and hampered cell proliferation at concentrations of 10-50 μg/ml and 100-250 μg/ml respectively, depending on the exposure duration. PS NPs did not significantly affect viability under the tested conditions (up to 250 μg/ ml). Next, cell cycle dynamics and differentiation capacity of the hDPSCs were assessed using a propidium iodide/phospho-histone H3 mitosis marker double staining and alizarin red S staining respectively. PS NPs did not cause any effects while TiO 2 NPs and PVP-AgNPs affected both parameters. At low doses proliferation was induced while at higher concentrations inhibition occurred. Similar findings were found for differentiation which was induced in response to TiO 2 NPs exposure in a dose-dependent manner and to Ag NPs depending on the dose and passage number. Underlying these effects, it was also shown that mitochondria were targeted by PVP-Ag and TiO 2 NPs during both processes. Exposure resulted in mitochondrial depolar-ization (JC-10 assay) and an alteration of mitochondrial morphology and number at several of the tested concentrations (Mitotracker CMXRos Red imaging and TEM). The current results suggest that both PVP-Ag and TiO 2 NPs might negatively affect development while PS NPs pose less threat. Because of the central role of mitochondria in both processes of proliferation and differentiation we aim to further explore the mechanisms by which NPs affect these important organelles and how downstream effects are triggered. Further research focusing on the sequence of events underlying the mitochondrial effects, will reveal if and how mitochondrial parameters can be used for biomarker development and future risk assessment strategies.

Jaar van publicatie:2022

Toegankelijkheid:Closed