Aplin, John D

Jauniaux, Eric

Jones, Carolyn JP

English

UCL Discovery

BJOG. 2023;00:1–4.    | 1wileyonlinelibrary.com/journal/bjoC O M M E N T A R YEnvironmental nanoparticles and placental researchJohn D. Aplin1,2  |    Carolyn J. P. Jones1,2  |    Eric Jauniaux31Division of Developmental Biology & Medicine, Faculty of Biology, Medicine and Health, School of Medical Sciences, University of Manchester, Manchester, UK2Maternal and Fetal Health Centre, St Mary's Hospital, Manchester, UK3Faculty of Population Health Sciences, EGA Institute for Women's Health, University College London (UCL), London, UKCorrespondenceJohn D. Aplin, Maternal and Fetal Health Centre, St Mary's Hospital, Manchester M13 9WL, UK.Email: john.aplin@manchester.ac.uk1 |  I N TRODUC TIONNanoparticles (NP) (usually understood as in the range 1–100 nm) are, in principle, capable of intercellular barrier penetration as well as ingestion by cells, particularly phago-cytes and transporting epithelia. Here we focus on particu-late black carbon (BC) and nanoplastics.Black carbon arises as a sooty paracrystalline insoluble product during combustion of wood, other plant material (including tobacco combustion products inhaled by smok-ers) or petroleum products in spaces with limited oxygen.1 It is used as a stabiliser in tyre manufacture, paints and pig-ments and as a food colourant. Particulate material from vehicle emissions is classified by size; for example, PM2.5 are NP <2.5 nm. Carbon NP are produced by design, too, for example as nanofibres or nanotubes. Routes of exposure are most likely to be via inhalation or ingestion. High expo-sures may occur as a result of vehicle emissions from nearby roads. Epidemiological studies have suggested associations between particulate air pollution (including PM2.5) and hy-pertensive disorders of pregnancy, growth restriction and preterm birth, but are often confounded by the presence of other pollutants.2Microplastics (around 1–100 mm) in the environment generally arise from pellets, packaging, personal protective equipment, textiles, tyres or fishing nets, either directly as a by-product of manufacturing or by mechanical, light-me-diated or biological fragmentation and degradation.3–5 They are already very widespread in soil and aquatic environ-ments, and concentrations are rising. Microplastics break down into nanoplastic particles which are more difficult to detect and quantify, and more likely to become incorpo-rated from air, water, soil or food into biological systems. In addition, primary nanoplastics are directly made for use in cosmetics, facial cleansing products, and air-blasting technologies. Data associating microplastics exposure with  abnormal pregnancy outcomes have started to appear in the literature.6Research is required to inform the updating of legislation to protect women as early as possible in their pregnancies, or ideally those planning a pregnancy. Within this context, epidemiology data supported by laboratory investigations are essential in understanding the placental transfer of NP and their impact on placental biological function and fetal development.2 |  HOW M IGHT NA NOPA RTICL E S I N TER AC T W ITH PL ACE N TA L TISSU E S?Nanoparticles in uterine or placental tissue compartments may cause adverse effects during pregnancy. Direct access of blood to the placental surface is limited during the first trimester,7 but early pregnancy effects on uterine function such as decidualisation are pertinent.8 From second tri-mester, particles might access the surface of chorionic villi, accumulate in the intervillous space, become incorporated into villous tissue or even cross the placenta to gain access to fetal blood and tissues. Human placental barrier thick-ness diminishes progressively over the course of pregnancy and in the third trimester may be only 3–4 μm, overlying fetal capillaries to form so-called vasculo-syncytial mem-branes. Ingestion of NP into syncytiotrophoblast may be via f luid phase pinocytosis, phagocytosis or endocytosis or via clathrin-coated vesicles for receptor-mediated up-take9 (Figure  1). Where the syncytial epithelium suffers local damage, as always occurs even in normal pregnancy, Accepted: 12 October 2023DOI: 10.1111/1471-0528.17695  This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.2 |   APLIN et al.a paracellular route into the placental villous mesenchyme and potentially fetal circulation is available across the fi-brinoid matrix, but this is limited to substances of rela-tively low molecular mass and is unlikely to be utilised by NPs. Intact syncytium has been reported to contain na-nopores that connect the maternal blood space with the area between the syncytial basal surface and the basement membrane;10 in principle these might offer a direct route of access for NPs (<10 nm) to the stroma.Uptake of microparticles by the placenta and evidence for translocation to the fetus in both human and various animals have been reviewed.11–13 In studies of other spe-cies, different barrier anatomy must be taken into account; the haemochorial placenta (seen in human, other primates, mouse, rat and rabbit) is unique in allowing direct access of blood-borne particles to trophoblast at the outer sur-face, though the number of tissue layers may vary. Accurate reporting of basic placental anatomy in the context of the particles detected is critical in assessing the barrier roles of different tissue layers and locations, optimising sampling protocols and evaluating the likelihood that NP might gain access to fetal tissues.14–173 |  TECH N ICA L ISSU E SDirect localisation in the tissue presents a technical chal-lenge that is greater with plastic NP than with carbon NP can be seen by transmission electron microscopy, though it may be difficult to distinguish from other electron-dense inclusions. Density is difficult to quantify in 3D tis-sues, and microscopic approaches require morphometry to estimate quantity of NPs at whole organ level. Efficient internalisation of particles by Hofbauer cells – placental macrophages – has been documented in vitro. Presence of NPs in amniotic f luid or cord blood18 can provide a high standard of evidence for transfer across the placenta but the inadvertent introduction of contaminating environmental NP during sample processing must be rigorously avoided. At present the route of transplacental transmission is un-clear.15,16 In some studies placental tissue was macerated, thus not allowing discrimination between fetal and mater-nal compartments or maternal blood retained in the inter-villous space at delivery.6,19,20 Another possible approach is to isolate specific single cell subpopulations from NP-exposed placentas for examination.Studies of particulate matter in placental cells in  vivo, in vitro and ex vivo show evidence of uptake by the syncy-tium.13,15,16 Experimental approaches are useful in building hypotheses regarding mechanisms of functional impair-ment. These include oxidative stress and DNA damage, altered occurrence of Hofbauer cells, and effects on trans-port, metabolism, endocrine function, growth, vascular de-velopment, coagulation and complement activation, barrier integrity, inflammatory status, the renin-angiotensin sys-tem, intraplacental signalling including protein kinase A and altered release of signalling substances to the fetus.12,13 Transfer within tissue, and more specifically across the pla-centa to fetal compartments, is affected by particle size, par-ticle material, weathering, charge and surface composition, dose and gestational stage of the model.13,21 Plastic NPs of varying size and surface charge have been tested in animals and in ex vivo dual perfusion studies in humans, where par-ticles up to 240 nm were taken up by the placenta.22Other studies suggest accumulation in the syncytium or in Hofbauer cells without further translocation.13 Thus F I G U R E  1  Diagram of a terminal villus of a human placenta showing the surface covered by microvilli at the base of which are clathrin-coated vesicles for receptor-mediated endocytosis and also macropinocytotic channels for f luid uptake, via which microparticles from the maternal blood in the intervillous space may also be ingested. Particulate matter would have to traverse the trophoblast and be discharged before penetrating both trophoblast and endothelial basal laminae plus the endothelium itself before entering the fetal circulation. Particles may also be taken up by mesenchymal cells rather than entering the fetal capillary. Precision is therefore crucial when characterising particle location in tissue, whether it be in the trophoblast, mesenchyme or endothelium as well as its position within the villous tree or chorionic plate.16 14710528, 0, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17695 by University College London UCL Library Services, Wiley Online Library on [01/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License   | 3PARTICLES AND PLACENTA RESEARCHan important component of the placenta's defence strategy involves ingestion and retention. The presence of particles in tissue, especially when this has been reported with-out quantification, does not justify an assumption that damage is occurring at a level that is consequential for pregnancy outcome. However, cell culture evidence has indicated cytotoxicity in trophoblast and BeWo cells, so the possibility that high levels of NP in syncytiotropho-blast could have a deleterious effect on placental function cannot be ignored.4 |  CONCLUSIONExposure to high levels of air pollution and microplastics can have an adverse effect on the fetus,23 possibly due to deterioration in placental endocrine, metabolic and im-munological functions, and a range of effects have been shown in animal models including altered growth and protein expression. There is also evidence that nanopar-ticulate material may bind viruses and facilitate their entry into cells. Well-controlled epidemiological and ex-perimental studies distinguishing direct and indirect ef-fects of NP are now required as well as determining the timing (early or late) of exposures in pregnancy. More sophisticated 3D models of the human placental barrier are also required. Appropriate use of animal species will enable the possible longer-term impacts on offspring to be evaluated. In human, effects may alter after 11 weeks of gestation with the onset of maternal blood f low to the placenta. Most work to date on transplacental transfer has focused on solutes, and so methods for the quantification and accurate tracing of particles into and across the pla-cental barrier need improving, including monitoring of location, accumulation and persistence in placental tissue, and metabolic and inf lammatory adaptation.AU T HOR C ON T R I BU T ION SAll authors contributed to the conception and writing up of this commentary.AC K NO W L E  D G E  M E N T SWe are grateful to Mr David Smithson, Senior Graphic Designer, UCL Digital Media, for his support in making the diagram. We acknowledge contributions by the numerous authors whom we were unable to cite due to limitations in the commentary format.F U N DI NG I N FOR M AT IONNone.C ON F L IC T OF I N T E R E S T S TAT E M E N TNone declared.DATA AVA I L A BI L I T Y S TAT E M E N TData sharing is not applicable to this article as no datasets were generated or analysed during the current study.E T H IC S A PPROVA LNone required.ORC I DJohn D. Aplin   https://orcid.org/0000-0001-8777-9261 Carolyn J. P. Jones   https://orcid.org/0000-0002-0026-9494 Eric Jauniaux   https://orcid.org/0000-0003-0925-7737 R E F E R E N C E S 1. Hopkins RJ, Tivanski AV, Morten BD, Gilles MK. Chemical bonding and structure of black carbon reference materials and individual car-bonaceous atmospheric aerosols. J Aerosol Sci. 2007;38(6):573–91. 2. Pedersen M, Stayner L, Slama R, Sorensen M, Figueras F, Nieuwenhuijsen MJ, et al. Ambient air pollution and pregnancy-in-duced hypertensive disorders: a systematic review and meta-analysis. Hypertension. 2014;64(3):494–500. 3. Schmidt R, Nachtnebel M, Dienstleder M, Mertschnigg S, Schroettner H, Zankel A, et  al. Correlative SEM-Raman microscopy to reveal nanoplastics in complex environments. Micron. 2021;144:103034. 4. Liu S, Lin G, Liu X, Yang R, Wang H, Sun Y, et al. Detection of various mi-croplastics in placentas, meconium, infant feces, breastmilk and infant formula: a pilot prospective study. Sci Total Environ. 2022;854:158699. 5. Yuan Y, Qin Y, Wang M, Xu W, Chen Y, Zheng L, et al. Microplastics from agricultural plastic mulch films: a mini-review of their im-pacts on the animal reproductive system. Ecotoxicol Environ Saf. 2022;244:114030. 6. Amereh F, Amjadi N, Mohseni-Bandpei A, Isazadeh S, Mehrabi Y, Eslami A, et al. Placental plastics in young women from general pop-ulation correlate with reduced foetal growth in IUGR pregnancies. Environ Pollut. 2022;314:120174. 7. Aplin JD, Lewis RM, Jones CJ. Development of the human placental villus. 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Int J Environ Res Public Health. 2020;17(23):8948. 14710528, 0, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.17695 by University College London UCL Library Services, Wiley Online Library on [01/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Environmental nanoparticles and placental research

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Environmental nanoparticles and placental research

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