On Placental Toxicology Studies and Cerium Dioxide Nanoparticles
Abstract
:1. Background
1.1. Human Placenta Ontogeny and Structure
- the villous cytotrophoblasts (VCTs), which differentiate into a syncytium called a syncytiotrophoblast (ST) by a cell-cell fusion process,
- the extravillous cytotrophoblasts (EVCTs), which invade the maternal decidua basalis up to the upper third of the myometrium, take part in the remodeling of the maternal spiral arteries and are responsible for the immune tolerance of the conceptus by expressing a non-classic human leucocyte antigen.
1.2. Human Placental Functions
1.3. The Placental Barrier
- an increase in the exchange surface area through the continuous ramifications of the villus tree to reach an area of 14 to 20 m2 at term;
- a decrease in the trophoblastic bilayer width, and therefore in the epithelial barrier between the maternal and fetal bloodstreams, dropping from 50 µm in the second month of pregnancy to 5 µm at the end of pregnancy;
- the arrival of maternal oxygenated blood in the intervillous chamber in contact with the ST between 10 and 14 WA after the removal of the trophoblastic plugs;
- an increase in the uterine blood flow up to 600 mL/min at the term of pregnancy.
- All these physiological changes must be considered when studying the effects of pollutants on the placental barrier and throughout placental ontogeny.
1.4. Impacts of Pollutants on the Human Placenta
2. Strategies to Study the Impact of Pollutants on the Placenta Barrier
2.1. Animal Models
- hemotrichorial placenta in rodents, composed of three trophoblast layers (one of VCT and two ST) instead of a trophoblast bilayer in humans (VCT and ST);
- the human placenta has several cotyledons on the maternal side of the placenta, unlike placenta in rodents;
- a labyrinthine organization (resulting from the fusion of villi around maternal blood gaps) in rodents;
- lack of hCG and of steroid hormone production by rodent placenta (e.g., steroids are secreted by the ovary during gestation);
- a more superficial invasion of maternal decidua in mice;
- the period of gestation (19–20 days for mice versus 270 days for humans).
2.2. Ex Vivo Placental Perfusion
2.3. Chorionic Villous Explant Cultures
2.4. Primary Culture of Trophoblasts (EVCT, VCT and ST)
2.5. Trophoblast Cell Lines
2.6. Co-Cultures and 2.5D Two-Chamber Models
2.7. Placenta-on-a-Chip Models
2.8. 3-D Models
3. Current Knowledge on Nanoceria
3.1. Introduction to Nanoparticles
3.2. Impact of Nanoparticles during Pregnancy
3.3. Nanoceria Properties
- As a pro-oxidant, in particular by the Fenton reaction, to kill cancer cells [103]
- As a carrier for targeted drug and gene delivery thanks to their coating ability and pH-dependent oxidation state, mainly in oncology therapies [104]
- As an antibacterial against Gram-positive and Gram-negative bacteria [105]
- In regenerative medicine and tissue engineering by enhancing long-term cell survival, enabling cell migration and proliferation and promoting stem cell differentiation [106].
3.4. Nanoceria and Human Health
3.5. CeO2 and Pregnancy
4. Discussion
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Models | Interests in Toxicology Studies | Advantages | Drawbacks |
---|---|---|---|
Animal models | • impact on pregnancy and outcomes • fetotoxicity studies | • in vivo • low cost • chronic exposure possible | • cautious extrapolation to animal model in view of the specificity of human placentation |
Ex-vivo placental perfusion | • transplacental passage • placental kinetics and metabolism • placental accumulation of pollutants | • access to organized placental tissue (a whole cotyledon perfused) | • only possible in term placentas • do not allow chronic exposure • nonplacental pharmacokinetic factors |
Chorionic villous explant cultures | • barrier permeability and tissular accumulation of pollutants • impact on cell viability • hormonal production | • physiological villi • near-physiological 3D microenvironment | • in vitro • fast ST necrosis • limited time exposures (less than 15 days) |
Primary human trophoblast cultures | • impact on trophoblast viability • hormonal production • cellular internalization of pollutants | • recapitulate physiological differentiation to form the syncytium • isolation from term and first trimester placentas | • in vitro • limited period of culture due to cell necrosis • not adapted for chronic exposure |
Cell line cultures | • impact on cell viability • cellular internalization of pollutants • cell signaling and hormonal production | • low cost • acquired resistance to apoptosis • possible adaptation to long term exposures | • in vitro • cancerous/immortalized cells’ properties distinct from physiological trophoblasts |
2D co-cultures and placenta-on-a-chip | • barrier permeability and bypassing • impact on cells’ viability • cell signaling and hormonal production | • near-physiological 3D microenvironment | • in vitro • cancerous/immortalized cells’ properties distinct from physiological trophoblasts |
3D models (organoids) | still under development | • recapitulate the human placenta villi • anatomically and functionally close to the villous placenta • long term culture possible (chronic exposure possible) | • in vitro • from first trimester placentas only • the polarity of the organoids (ST within the organoid cavity) needs to be reversed for toxicological studies. |
Model | Sandwich Culture | Transwell Insert | Placenta-on-a-Chip System |
---|---|---|---|
Authors | Nishiguchi et al. 2019 [58] | Aengenheister et al., 2018 [56] | Blundell et al., 2018 [65] |
http://creativecommons.org/licenses/by/4.0/, accessed on 10 November 2021 | |||
Villous cytotrophoblasts | primary VCTs (third trimester) with collagen and laminin coating | BeWo b30 | BeWo b30 |
Villous endothelial cells | human umbilical vein endothelial cells (HUVECs) with fibronectin and gelatin coating | microvascular human placental venous endothelial cell line (HPEC-A2) | human primary placental villous endothelial cells (HPVECs) |
Villous mesenchymal fibroblasts | primary human villous mesenchymal fibroblasts (HVMFs) with fibronectin and gelatin coating | none | none |
Technology | bottom-up approach using ECM (extracellular matrix) nanofilms | polycarbonate Transwell insert | upper and lower microchannels separated by a thin, semipermeable membrane |
Description of the model |
Model | 3D Spheroids | Organoids |
---|---|---|
Author | Muoth 2016 | Turco 2018 |
Villous Cytotrophoblast | BeWo b30 and HTR-8/SVneo | Primary first trimester (8 to 11 WA) proliferative trophoblasts |
Villous mesenchymal fibroblasts | Primary human villous mesenchymal fibroblasts (HVMF) | none |
Technology | Scaffold-free hanging drop technology (GravityPLUS plates) | Isolation of first trimester proliferative trophoblasts seeded in drops of matrigel in a basal culture medium for the formation of organoids, including growth factors and inhibitors |
Description of the model |
Ce3+ → Ce4+ | |||
---|---|---|---|
Oxidation of Ce3+ | O2 + Ce3+ | → | O2•– + Ce4+ |
•OH + Ce3+ | → | OH− + Ce4+ | |
OH− + H+ →H2O | |||
Superoxide Dismutase (SOD) mimetic activity | O2•– + 2H+ + Ce3+ | → | H2O2 + Ce4+ |
Fenton-like reaction | H2O2 + Ce3+ | → | •OH + OH− + Ce4+ |
Catalase (CAT) mimetic activity | H2O2 + 2H+ + 2Ce3+ | → | 2H2O + 2Ce4+ |
Ce4+ → Ce3+ | |||
Reduction of Ce4+ | H2O2 + Ce4+ | → | H+ + HO2 + Ce3+ |
Superoxide Dismutase (SOD) mimetic activity | O2•– + Ce4+ | → | O2 + Ce3+ |
Catalase (CAT) mimetic activity | H2O2 + 2Ce4+ | → | 2H+ + O2 + 2Ce3+ |
Data Sources | Model Used | Nanoceria Effects | Type of Nanoceria | Dose and Time Exposure |
---|---|---|---|---|
Nedder et al. 2020 | Primary VCTs from human placentas at term of pregnancy | Internalization in both VCT and ST Dose and time dependent cytotoxicity Decrease in differentiation to form the ST Disrupted hormonal production Caspase activation | NM-212 (Joint Research Center nomenclature) polyhedral 28.4 ± 10.4 nm aggregate size 503 ± 55 nm | from 0.1 to 101 µg/cm2 until 72 h |
Zhong et al. 2020 | BALB/c mice | Altered decidualization: disruption of decidual cell secretion of regulators of trophoblast invasion, altered uterine natural killer (uNK) cell recruitment and differentiation Decrease in birth weight Smaller litters because of failure in the fetus development | 3−5 nm | 5 mg/kg intravenous once a day at on D5, D6 and D7 |
Paul et al. 2017 | C57BL6/J mice | Long-lasting impairment of lung development of the offspring Significant decrease in vascular endothelial growth factor (VEGF) mRNA and protein levels in amniotic fluid and pup lungs Significant decrease in fetal weight and placental efficiency | spherical shape 22.4 ± 0.2 nm aggregate size >1000 nm | intratracheal instillation of 300 µg (100 µg by week) on pregnant mice |
Vafaei-Pour et al. 2018 | Swiss albino mice with diabetes induced by one dose of intraperitoneal injection of streptozotocin (60 mg/kg) | Reverse the elevation of oxidative stress markers induced by diabetes Diabetes-induced malformation in visceral and spinal of embryo partially restored | no data | 60 mg/kg for 16 days |
Lee et al. 2020 | Sprague-Dawley rats | Cerium was not detected in either parental or pup tissues, not systemically absorbed in parental animals or their pups | polyhedral 14.2 ± 5.0 nm | 100, 300 and 1000 mg/kg orally administered during premating, mating, gestation and early lactation periods |
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Deval, G.; Boland, S.; Fournier, T.; Ferecatu, I. On Placental Toxicology Studies and Cerium Dioxide Nanoparticles. Int. J. Mol. Sci. 2021, 22, 12266. https://doi.org/10.3390/ijms222212266
Deval G, Boland S, Fournier T, Ferecatu I. On Placental Toxicology Studies and Cerium Dioxide Nanoparticles. International Journal of Molecular Sciences. 2021; 22(22):12266. https://doi.org/10.3390/ijms222212266
Chicago/Turabian StyleDeval, Gaëlle, Sonja Boland, Thierry Fournier, and Ioana Ferecatu. 2021. "On Placental Toxicology Studies and Cerium Dioxide Nanoparticles" International Journal of Molecular Sciences 22, no. 22: 12266. https://doi.org/10.3390/ijms222212266