Nanoparticles at the maternal-fetal interface

Abstract

The increasing production of intentional and unintentional nanoparticles (NPs) has led to their accumulation in the environment as air and ground pollution. The heterogeneity of these particles primarily relies on the NP physicochemical properties (i.e., chemical composition, size, shape, surface chemistry, etc.). Pregnancy represents a vulnerable life stage for both the woman and the developing fetus. The ubiquitous nature of these NPs creates a concern for developmental fetal exposures. At the maternal-fetal interface lies the placenta, a temporary endocrine organ that facilitates nutrient and waste exchange as well as communication between maternal and fetal tissues. Recent evidence in human and animal models identifies that gestational exposure to NPs results in placental translocation leading to local effects and endocrine disruption. Currently, the mechanisms underlying placental translocation and cellular uptake of NPs in the placenta are poorly understood. The purpose of this review is to assess the current understanding of the physiochemical factors influencing NP translocation, cellular uptake, and endocrine disruption at the maternal-fetal interface within the available literature.

1. Introduction

The World Health Organization (WHO) defines air pollution as the contamination of the indoor or outdoor environment by any chemical, physical, or biological agent that modifies the natural characteristics of the atmosphere. Included in air pollution is particulate matter (PM), consisting of liquid or solid droplets that are suspended in the air. These particles are fractionated by size as described by EPA standards (i.e., PM₁₀, PM_2.5, and PM_0.1) which correlate to the particulate aerodynamic diameters of less than 10 μm, 2.5 μm, and 0.1 μm, respectively. In laboratory studies, micro particles are categorized as particles with a single dimension less than 5 μm. Nanoparticles (NPs) and ultrafine particulate matter (PM_0.1) are both defined by a diameter of less than 0.1 μm in a single dimension. NPs elicit differing physicochemical properties than their larger microparticle counterparts. These include composition, size and shape, charge, dissolution, agglomeration, surface chemistries, and protein corona that can impact the biological interactions with these small particles following exposure (Sharifi et al., 2012; Gubala et al., 2018; Khan et al., 2019; Aengenheister et al., 2021). Often the NP properties have been identified as being more toxic than the larger particles. As it has been estimated that over 90% of airborne PM is comprised of NP (Kwon et al., 2020) it is crucial to understand their hazard potential in human populations.

Sensitive populations may be at a higher risk of developing adverse effects of air pollution. In this paper we will focus on pregnancy as a life stage, where exposure may affect the mother and developing fetus. The placenta is a transient, temporary organ of fetal origin that acts as an interface between the maternal and fetal circulations in many mammalian species. It also provides several functions to support fetal growth and development including, endocrine, immune, and metabolic processes (Herrick and Bordoni, 2022).

The systemic effects of air pollution exposure, those occurring outside of the pulmonary system, have been theorized to occur through neurological, inflammatory, and particle translocation allowing for local particle-cellular interactions (Araujo, 2010). Impaired neurological signaling and systemic inflammation would undoubtedly impact placental function and fetal development. For the purposes of this review we will limit our scope to focus on the placenta as a target organ for nanoparticle translocation to provide a better understanding of the local and direct effects of nanoparticle exposure during pregnancy. Thus, the purpose of this review is to highlight the placenta as an endocrine organ, describe the physiochemical properties of nanoparticles, and discuss NP influence cellular uptake and dysfunction, including endocrine disruption to aid in determining the etiology of NP induced impairments during pregnancy.

2. The placenta

The placenta is a unique and temporary organ that acts as a semipermeable barrier between the maternal and fetal compartments during pregnancy. This tissue allows for separation of the maternal and fetal circulations, thus preventing the direct mixing of blood and immunological factors, while permitting nutrient and waste exchange. The placenta is also an endocrine organ producing and responding to hormonal agonists. Proper functioning placenta is crucial to ensure the success of pregnancy and fetal development.

2.1. Anatomy

Placenta are characterized by their structure and anatomy, gross shape, and histological characteristics which may vary greatly between species. In humans, rats, and mice the mature placenta is hemochorial, discoid in shape, and functions as the site for nutrient and waste exchange, metabolism, fetal protection, and production of hormones (Burton and Fowden, 2015; Soncin et al., 2015; Roberts et al., 2016). Overall, the placenta consists of a maternally derived decidua formed of specialized cells from the endometrium, an intermediate portion identified as the intervillous space, and a fetal derived portion, termed the chorion or chorionic sac (Fig. 1) (Grube et al., 2005; Furukawa et al., 2014). Descriptions of rodent placenta are often divided into three zones: maternal decidua, junctional zone, and labyrinth (Fig. 1). The labyrinth zone contains the chorionic villi that function as the site of nutrient and gas exchange (Woods et al., 2018; Furukawa et al., 2011).

Fig. 1.

Discoid, hemochorial placental anatomy.

The chorionic villi consists of three distinct cell layers: the outermost maternal facing syncytiotrophoblast, the cytotrophoblast of the villus, and the extravillous trophoblast (Herrick and Bordoni, 2022; Furukawa et al., 2014; Turco and Moffett, 2019). The syncytiotrophoblast is in direct contact with maternal glandular secretions and maternal blood as it flows into the intervillous space (Furukawa et al., 2014; Turco and Moffett, 2019). Beneath the syncytiotrophoblast lies the stem-like cytotrophoblast cells on the basement membrane. These cells serve to replenish the syncytiotrophoblast and extravillous trophoblast cells. During placental development, the extravillous trophoblast cells migrate into the decidua through the stroma towards the maternal spiral arteries. This step allows for spiral artery remodeling, supporting the necessary increase in blood flow during pregnancy (Turco and Moffett, 2019). The fetal portion of the placenta consists of the fetal facing amnion and the fetal facing chorion. The chorion is made of the reticular layer, a basement membrane and a trophoblast layer (Grube et al., 2005). Overall, the maternal and fetal layers of the placenta are comprised of specialized cells that work together to perform the major barrier, exchange, and transport functions of the placenta.

In hemochorial placenta maternal blood enters through the spiral endometrial artery over the chorionic villi within the intervillous space (Grube et al., 2005; Turco and Moffett, 2019; Kapila and Chaudhry, 2022). The chorionic villi are lined by cyto- and syncytiotrophoblast cells, which increase surface area to maximize the efficiency of nutrient and waste exchange (Burton and Fowden, 2015; Grube et al., 2005; Turco and Moffett, 2019; Kapila and Chaudhry, 2022). Human placenta are separated by a single layer of syncytiotrophoblast cells with cytotrophoblast support; whereas the maternal and fetal circulations of rats and mice are separated by three trophoblast layers, one syncytiotrophoblast layer and two derived of cytotrophoblast cells (Shojaei et al., 2021). Notably, placental exchange in the mouse occurs between these cellular layers, identified as the labyrinthine, whereas placental exchange in humans occurs in the villous (Carter, 2007).

2.2. Physiology

The placenta facilitates nutrient and waste exchange, functions as an endocrine organ allowing for maternal-fetal communication, and has immune functions capable of fetal protection (Kapila and Chaudhry, 2022). Many mechanisms exist within the placenta to maintain homeostasis during pregnancy, as well as promote growth and development of the fetus. For example, finger-like projections of the chorionic villi maximize nutrient and waste exchange by increasing placental surface area and allowing for higher metabolic capacity to satisfy increased demand as the fetus develops throughout pregnancy (Grube et al., 2005; Turco and Moffett, 2019; Kapila and Chaudhry, 2022).

Placental transporters facilitate the bidirectional transport of nutrients and waste across the trophoblast layer(s). Transporters within the placenta fall into two main families: the ATP- binding cassette (ABC) and solute carrier (SLC) families (Walker et al., 2017). These proteins play a role in the exchange of nutrients and waste including folate, cholesterol, thyroid hormones, prostaglandin, and lactate, while inhibiting the transport of toxic chemicals and xenobiotics (Walker et al., 2017). P-glycoprotein (PGP), breast cancer resistance protein (BCRP), and multidrug resistance protein-1 (MRP-1) have also been established as transporters within the human placenta (Leslie, Deeley Rg Fau - Cole and Cole, 2005).

Furthermore, the placenta produces a variety of hormones to support and maintain pregnancy thus acting as an endocrine organ. Trophoblast cells promote the majority of endocrine function and hormonal production. Syncytiotrophoblast cells are responsible for the production of human chorionic gonadotropin (hCG) during implantation to establish and maintain pregnancy, and to inhibit circulating hormones of the reproductive cycle (Kapila and Chaudhry, 2022; Costa, 2016). They also produce human placental lactogen (HPL), which regulate metabolisms, ensures fetal nutrition, and stimulates the growth of breast tissue to prepare for lactation (Kapila and Chaudhry, 2022). HPL regulates energy homeostasis between the mother and baby by promoting maternal lipolysis and carbohydrate metabolism (Costa, 2016). Placental growth hormone (PGH) is predominately produced from the syncytiotrophoblast cells along with extravillous trophoblast cells (Costa, 2016; Lacroix et al., 2002). PGH plays an essential role in regulation of placentation, and acts as a surrogate for pituitary-derived growth hormone prior to fetal pituitary development (Lacroix et al., 2002). Steroid hormones, including progesterone (P₄) and estrogen (E₂) are produced from the syncytiotrophoblast cells and are necessary for the maintenance of pregnancy. Progesterone acts to ensure uterine receptivity to the embryo, initiate decidualization, and plays a role in maternal immune tolerance to the developing fetus (Costa, 2016). Placental-derived estrogens act to increase the utero-placental blood flow, promote implantation of the embryo, and stimulate endometrial growth and differentiation (Costa, 2016). Lastly, adipokines, such as leptin and adiponectin, are also produced from the syncytiotrophoblast cells, and are critical to prepare the maternal body for dynamic metabolic changes to support the growing fetus. Thus, the placenta acts as a vital endocrine organ to support and maintain pregnancy, as well as the growth and development of the fetus.

2.3. Species differences and alternative methods

In addition to the anatomical structural differences between humans and rodents, the endocrine profile of the placenta, and subsequent processes of implantation and placentation, differs between humans and rodents (Carter, 2007; Schmidt et al., 2015). While mouse trophoblastic invasion is shallow and limited to the proximal decidua, human trophoblast invasion of uterine arteries is quite extensive (Carter, 2007). The process of placentation is heavily influenced by hormonal control and differs between rodents and humans. While mice require ovarian progesterone production from the corpus luteum (CL) throughout pregnancy, maintained by prolactin production from the pituitary at first and later by placental lactogen, human CLs are maintained by hCG production from the trophoblast cells (Carter, 2007). Mice also lack other specific characteristics that are vital to human placental development, including hyperglycosylated chorionic gonadotropin, luteinizing hormone/choriogonadotropin receptor with exon 6a, estrogen synthesis, and biosynthetic hormone aromatase (Schmidt et al., 2015). These molecular differences make human extrapolation from rodent models challenging. Additional readings pertaining to placental difference across species can be found in these publications (Furukawa et al., 2014; Carter, 2007; Schmidt et al., 2015).

Alternative methods using in vitro and ex vivo human placental models have also been developed to combat the obstacles set forth in vivo studies (21–27). The placenta is a very unique organ across species, and thus specific considerations must be made when designing studies to investigate placental function. The ex vivo human placental perfusion model allows the researcher to isolate a single human cotyledon or single chorionic villious tree to test exchange and function (Aengenheister et al., 2021; Bongaerts et al., 2021; Aengenheister et al., 2019; Grafmueller et al., 2015; Wick et al., 2010). 3D human placenta-on-a-chip models utilize cellular microchannels containing trophoblast and endothelial cells, to mimic the placental barrier and microenvironment of the placenta (Yin et al., 2019). Other microfluidic systems have also been developed to study the unique maternal-fetal interphase of the human placenta (Gresing et al., 2021; Abostait et al., 2022). These placental chip and microfluidic models may better mimic the microenvironment of the human placenta, including the sheer stress exerted on the trophoblast cells, and syncytialization (Abostait et al., 2022). Lastly, in vitro cellular models may often be utilized to mimic the cellular environment and assess transcriptional differences.

3. Particulate matter

Particulate matter (PM) refers to either solid particles or liquid droplets suspended in the air. Currently, the United States Environmental Protection Agency (EPA) classifies PM into three categories based on their size: (1) course particles visible by the naked eye, termed PM₁₀, measuring less than 10 μm in diameter (e.g., pollen, dust, and mold); (2) fine particles that create a smoky or hazy appearance, termed PM_2.5, measuring less than 2.5 μm in diameter (e.g., combustion products including diesel exhaust or wood smoke); (3) ultrafine particles or NPs, PM_0.1, measuring less than 0.1 μm in diameter and are invisible to the naked eye. As ultrafine particles and nano-sized particles are defined as measuring less than 0.1 μm in diameter, we will refer only to NP from this point.

Currently, the EPA recognizes and regulates human exposure to PM_2.5 as harmful constituents of air pollution although current research provides evidence that PM_0.1, may have elevated toxicities when compared to their larger counterparts (Kwon et al., 2020; Schraufnagel, 2020). Moreover, it has been estimated that over 90% of airborne PM is comprised of NP (Kwon et al., 2020). The small size of NPs allow them to reach deeper portions of the lung after inhalation, increasing the likelihood of systemic transfer (Moreno-Rios et al., 2022); however, these particles are also much more difficult to consistently measure and regulate because of their small size.

3.1. Sources of NPs

NPs are generated by either intentional or unintentional means. Intentional NP are produced as homogeneous particles developed for their specific physicochemical properties at this small size for use in commercial applications (i.e., electronics, medical devices, personal care products), whereas unintentional NP are naturally derived through biochemical reactions and anthropogenic source including combustion, incineration, volcanic activity, weather events, or mechanical degradation (Buzea et al., 2007; Sonwani et al., 2021; Smita et al., 2012).

While many studies have focused on inhalation exposure to aerosolized NPs, it is important to note that humans may also be exposed to NPs through ingestion, injection, and dermal applications. Nanoenabled products are often intentionally included in personal care and food products as a color additive. Recently the EU removed the use of E171, nanotitanium dioxide (nano-TiO₂), as a food additive due to inflammatory concerns and neurotoxicity (Belder, 2022; Additives et al., 2021).

3.2. Maternal exposure

Pregnancy is a vulnerable life stage for both the mother and the developing fetus. During pregnancy there are significant adaptations to maternal physiology to support homeostasis during gestation. These include an increase to maternal cardiac output, plasma volume, tidal volume, glomerular filtration, and liver metabolism while reducing gastric mobility (Costantine, 2014). These physiological modifications will directly affect particle kinetics after exposure. Furthermore, current evidence suggests that plastic and metallic microparticles and NPs introduced during pregnancy in human and laboratory models, have the propensity to translocate out of the site of primary exposure, reach and cross the placenta, depositing in fetal tissues (Ragusa et al., 2021; Fournier, D’Errico, Adler et al., 2020; Cary et al., 2023; Campagnolo et al., 2017; D’Errico et al., 2022). In the next session of this review we will focus on NP susceptibility to translocate to the placenta.

4. Physiochemical properties affecting NP translocation

NP toxicity is based on particle physiochemical properties that make them unique as compared to larger particles of the same composition (Sharifi et al., 2012). Physiochemical properties including chemical composition, size and shape, charge, dissolution, agglomeration, surface chemistry/functional groups, and protein corona which may impact local cellular interactions, including oxidative stress, inflammation, particle uptake, internalization, and toxicity (Sharifi et al., 2012; Gubala et al., 2018; Aengenheister et al., 2021). NP may also be classified as organic, inorganic, metallic, metal oxide, polymeric, lipid, or biological (Khan et al., 2019).

4.1. Composition

Chemical composition defines a particles ability to interact with biological tissues. The chemical construct of each NP dictates the biological interactions and cellular toxicity. These toxicities are often associated with particle dissolution leading to oxidative stress or hydrogenation. NPs in many compositions have been demonstrated to translocate to the placenta in human and rodent models (Ragusa et al., 2021; Fournier et al., 2020; Campagnolo et al., 2017; D’Errico et al., 2022; Teng et al., 2019; Dusza et al., 2022; Kloet et al., 2015; Wang et al., 2020; Semmler-Behnke et al., 2014; Poulsen et al., 2015; Liu et al., 2016). Yet, few studies have investigated the impact on placental cell or trophoblast toxicity. In vivo studies investigated the effects of particle composition on translocation and fetal toxicity, as evidenced when pregnant BALB/c mice were injected with Si NPs of various sizes, nano-TiO₂, or fullerene (C60) particles, there were distinct compositional effects (Yamashita et al., 2011). Fullerene (C60) nanoparticles did not induce the same fetal resorptions and fetal growth restrictions that were observed following exposure to 70 nm nanosilica (nSP70) particles and 35 nm nano-TiO₂ particles, providing evidence that maternal-fetal toxicity is influenced by the composition of the NPs (Yamashita et al., 2011). Studies exposing mice to Cu NPs via inhalation throughout gestation (gestational day [GD] 3–19) were not found to translocate the placenta or reach fetal tissues as measured by ICP-MS (Adamcakova-Dodd et al., 2015). Interestingly, a similar inhalation exposure of nano-TiO₂ utilizing pregnant Sprague-Dawley rats (GD 4–19), identified titanium translocation to the placenta and fetal tissues via ICP-MS (D’Errico et al., 2022). It is unclear if the differences between these rodent studies are due solely to chemical, animal model, or functionalized group. These studies identify particle translocation to, and often across, the placental barrier indicating local and direct cellular-NP interaction. Therefore, it is evident that chemical composition affects translocation as well as the ability for NPs to elicit toxicity and should be considered when designing nanotechnologies and for setting safe exposure limits.

4.2. Size and shape

Particle size also effects NP translocation and cytotoxicity. In vitro studies have reported that smaller particles are more likely to exploit cellular transport pathways, resulting in elevated toxicities compared to micro- or larger particles (Shen et al., 2022; Huang et al., 2015). These evaluations have identified that PS NP cross the placenta in a size dependent manner, wherein particles up to 500 nm crossed the placental barrier at a lesser extent than smaller PS particles (Shen et al., 2022; Huang et al., 2015). Furthermore, cytotoxicity in studies of human placental choriocarcinoma JEG-3 cells were identified to be size and charge dependent, with the smallest PS NPs, 25 nm, exhibiting the most severe cytotoxicity regardless of the charge or surface modification (Shen et al., 2022). Studies utilizing an ex vivo human placental perfusion model have also identified that particle size directly effects PS NPs translocation across the placental barrier and reaching fetal perfusates (Grafmueller et al., 2015; Wick et al., 2010). It is important to note that there is disparity in the size restricting capacity of the placenta to PS NP using the ex vivo human placental perfusion model, where one study found no larger than 50 nm (Grafmueller et al., 2015) could cross the placenta to reach fetal perfusates, while another found PS NPs up to 240 nm could reach fetal perfusates (Wick et al., 2010).

Size-dependent placental transfer of nanoparticles has also been investigated in vivo in pregnant rodents (Teng et al., 2019; Semmler-Behnke et al., 2014; Yamashita et al., 2011). Oral administration of 13 nm ZnO particles, compared to its 57 nm and bulk counterparts, could more easily pass through several biological barriers, following oral gestational exposure resulting in size-dependent placental dysfunction and fetal toxicities (Teng et al., 2019). Intravenous injection of Au NPs also elicited size specific placental translocation and toxicity, with a higher accumulation of the smallest radio-labeled particles that the larger composites (Semmler-Behnke et al., 2014). Collectively, these studies suggest that regardless of exposure route and composition, in vivo gestational exposure to NPs exhibits size dependent translocation and toxicity in rodent models.

Shape of particles of the same composition has not been widely considered in toxicological studies. NPs may be represented as intentionally produced spheroids, as are PS beads, or spear-like single-/multiwalled carbon nanotubes. Environmental NP are often multi-faceted, often containing angular areas. Each of these NP would engage with cellular membranes in a different capacity. Sphered objects may be of little concern, whereas long tube structure may pierce lipid membranes or result in incomplete macrophage engulfment. Interestingly, all of these shapes have been shown to translocate from the original site of origin; however, the placenta has not been consistently evaluated (Fournier et al., 2020; Campagnolo et al., 2017; Stapleton et al., 2012). While shape has not been a widely studied property, it should be considered as it pertains to NP studies.

Overall, available research provides evidence that particle translocation is size dependent (Grafmueller et al., 2015; Wick et al., 2010; Semmler-Behnke et al., 2014; Shen et al., 2022; Huang et al., 2015), with a greater accumulation of smaller particles. This highlights the increasing concern regarding NP, as compared to microparticles, exposure during pregnancy. At this point, a size cutoff for placental translocation has yet to be determined. This is especially necessary in real-world models of ingestion and inhalation as these studies require the breach of multiple physiological barriers to reach the placental and fetal tissues. Therefore, particle size remains a key player in determining the extent of placental translocation and toxicity.

4.3. Charge

NP charge will affect cellular membrane interactions, thus impacting the local environment and uptake. Few studies have investigated how particle charge may influence placental tissues. Positively charged NPs in vitro were shown to increase particles translocation resulting in elevated toxicities due to strong ionic interactions with cellular membranes, allowing for more successful translocation, and elevated cytotoxicity (Shen et al., 2022). However, studies conducted in a microfluidic system found that negatively charged nanoparticles also had the ability to cross the placental barrier (Gresing et al., 2021). In vitro and ex vivo exposure to TiO₂ NPs with surface modifications of amine (i.e., positive charge) or carboxylate (i.e., negative charge) groups, resulted in cellular uptake, regardless of modification; however, amine modified TiO₂ NPs occupied a higher of fraction within these cells (Aengenheister et al., 2019). Small, positively charged NPs or functionalized with the addition of NH₂ groups, have been shown to have higher levels of translocation and elevated cytotoxicity (Shen et al., 2022; Abdelkhaliq, van der Zande, Peters et al., 2020). This may be attributed to strong ionic interactions that may occur between NPs with cellular membranes and organelles. Interestingly, the effects of charge and surface modifications may be secondary to composition and size (Aengenheister et al., 2019). These studies indicate that charge may influence placental translocation, cellular uptake, and toxicity, but the direct effects on placental tissues remain unclear.

4.4. Dissolution

Dissolution is the ability for solutes, or NPs, to dissolve in a solvent and form a new solution from the release of toxic ions and/or precipitates (Sharifi et al., 2012; Nel et al., 2009). Evidence of NP dissolution in biological systems have been reported in a variety of models after exposure to ZnO or Ag NP including immortalized murine macrophage cells, human bronchial epithelial cells, BeWo b30 placental cells, and using an ex vivo human placenta perfusion and ICR mice (Teng et al., 2019; Abdelkhaliq et al., 2020; Xia et al., 2008; Vidmar et al., 2018). It has been established that the dissolution of iron containing NPs can result in oxidative stress via activation of Fenton reactions, although this has not been identified in a placental model (Sharifi et al., 2012; Wu et al., 2014). Similarly, an in vivo study showed that ionic Ag may be more toxic than its Ag NP counterpart in Sprague Dawley rats (Charehsaz et al., 2016). The rate of NP dissolution must be considered as it can be heavily influenced by many factors, including the presence of proteins and organic substances and can dictate the toxicity (Xia et al., 2008). Although there is no evidence to directly support that dissolution plays a role in NP-induced placental toxicity, these studies provide evidence that dissolution influences toxicity in other systems, and thus suggest that similar mechanisms may exist in the placenta.

4.5. Agglomeration

Agglomeration is a phenomena by which particles can form bonds with each other resulting in an increased particle size and reduced accessible surface area, as compared to individual single particles. Agglomeration may occur within the environment, during exposure as particles interact, or once particles have deposited within a biological system. NP agglomeration heavily influences cellular interactions, including uptake and translocation, thereby impeding the ability to translocate to secondary organs following exposure (Poulsen et al., 2015; Aengenheister et al., 2018; Qi et al., 2014). For example, multi-walled carbon nanotubes intravenously injected into pregnant mice have also been shown to agglomerate after in vivo exposure, attributing the low absorption of NPs to the amounts of agglomerated particles (Qi et al., 2014). However, it is unclear if this agglomeration took place within the mouse or within the needle, prior to injection. During in vitro or ex vivo studies, particle agglomeration may be responsible for low cellular uptake. In laboratory studies, agglomerates of Rhodamine-labeled silica NPs formed in the outer surface of the chorionic villi during experiments using an ex vivo placental perfusion model (Poulsen et al., 2015), it is unclear if this outcome also occurs during physiological perfusion. The formation of larger agglomerates may be responsible for reduced placental translocation of Au NPs, as those studies utilizing carboxylated, as opposed to PEGylated NPs, that had a higher rate of translocation (Aengenheister et al., 2018). These studies reveal the ability of a particle to agglomerate in culture media and biological systems is likely a major determinant of particle translocation and nanotoxicity.

4.6. Surface chemistry/functionalized groups

The addition of functionalized groups (i.e., PEG, amine, carboxyl) to the surface of a NP, changes the chemical/biological behavior of the particle. These additions are intentional to assess particle behavior under specific conditions, for example to reduce agglomeration (see above) or to modify the particle charge to enhance cellular uptake. As identified above, surface modifications of TiO₂ NPs by adding and amine (i.e., positive charge) or carboxyl (i.e., negative charge) group, resulted in greater amine modified TiO₂ NP uptake (Aengenheister et al., 2019). PEG modification has been shown to alter the ex vivo transfer of Au NPs (Myllynen et al., 2008). In vitro studies of placental BeWo cells are conflicting, with studies reporting that particle coatings have no effect or that surface coating was a major influencer of NP uptake and cytotoxicity (Dusza et al., 2022; Abdelkhaliq et al., 2020). It is important to note that these studies were completed with Ag or PS NP; therefore the particle chemistry should be viewed as a confounding variable when making comparisons between the studies. Few studies investigate the effects of NP surface functionalized groups within the placenta and its relation to toxicity; however, these studies provide preliminary evidence that the surface chemistry of a particle is an important factor that influences how a particle will interact at the placental barrier. These types of modifications are highly valuable in the development of nano-medical drug delivery constructs.

4.7. Protein corona

A protein corona is a unique, spontaneous surface modification, which develops during as a particle enters a biological system. This results in the formation of a biomolecular shell or corona, composed of proteins, lipids, sugars, nucleic acids, and metabolites onto nanomaterial surface (Mahmoudi et al., 2023) Upon exposure, the NP becomes coated with biomolecules, forming a protein corona (Monopoli et al., 2012; Gruber et al., 2020; Tenzer et al., 2013). As the particle translocate from different organs, it has the ability to form different and more complex protein coronas (Gruber et al., 2020). For example, the surfactant in the lung has a different molecular profile than that of the interstitial fluid or blood plasma, which would create a uniquely layered protein corona on the surface of the NP. By contrast, if this same NP was directly injected into the venous circulation, the protein corona would include molecules only from the blood plasma, not the lung surfactant. The formation of these protein coronas can alter the way a NP engages with biological tissues, and has the ability to influence translocation and pathophysiology (Gruber et al., 2020; Tenzer et al., 2013). The development of these protein coronas are species specific, making it difficult to study in animals and extrapolate to humans (Solorio-Rodríguez et al., 2017). Thus the protein corona, and corona composition, plays an important role in dictating particle translocation.

Lastly, smaller particles, by definition, have a larger surface area thus allowing for greater interactions within the external and biological environment(s). As studies of environmental NPs or “real-world” samples continue, the risk associated with chemical adsorption becomes evident. This concern identifies NPs as a potential vector for local cellular exposure to noxious compounds including heavy metals and plasticizing chemicals.

5. Local cellular toxicity

NPs entering the placenta have three fates: to continue passage through maternal blood spaces via the cardiovascular system, trophoblast uptake, and local cellular toxicity. In this section, we will review the mechanisms of cellular uptake and the local cellular interactions between NPs and trophoblast cells. These interactions can lead to activation of apoptosis (Huang et al., 2015; Hu et al., 2022; Li et al., 2022; Nedder et al., 2020), autophagy, inflammation, oxidative stress, and genotoxic effects within the placenta. Cellular impairments can promote placental dysfunction and poor pregnancy outcomes, as well as embryonic and fetal toxicities. Below we review the evidence of cellular interactions within the placenta following NP exposure and a summary of the currently accepted cellular interactions that occur at the placenta following exposure to NPs depicted in Fig. 2.

Fig. 2.

Summary of cellular interactions that occur in the placenta, following gestational exposure to NPs. Created using BioRender.

5.1. Uptake

Several mechanisms of NP transport have been proposed, include diffusion, vesicular transport, active transport, transporter mediated, and through trans-trophoblastic channels (Grafmueller et al., 2015; Wick et al., 2010; Kloet et al., 2015; Semmler-Behnke et al., 2014). Given the tight cellular junctions and trophoblast layers within the placenta, NPs are unlikely to passively diffuse through the placenta. Therefore, it is likely that passage occurs through energy dependent mechanisms in combination with transporter proteins.

In vitro studies have identified that only positively changed PS NPs are able to exploit the MRP-1 transporter to gain access to the placenta and fetal compartments (Kloet et al., 2015). Human studies of ex vivo placental perfusion demonstrate that placental uptake of nanosized PS beads occur via energy dependent mechanisms (Grafmueller et al., 2015; Wick et al., 2010). Results from these studies provide supporting evidence that cellular uptake of PS NPs is likely energy dependent (Grafmueller et al., 2015), possibly through energy or vesicle dependent transport (Wick et al., 2010), despite confounding variables.

In vivo investigations conducted in pregnant mice demonstrate that metallic particles translocate the placenta via endocytosis (Wang et al., 2020; Rattanapinyopituk et al., 2014). Furthermore, exposure to Au NPs increased the production of clatherin proteins, likely indicative of clatherin-mediated endocytosis activation (Rattanapinyopituk et al., 2014). Exposure to ZrO₂ induced the expression of not only clatherin, but caveolin and afr6, also involved in endocytic pathways (Wang et al., 2020). Particles derived from pullulan acetate, water-soluble polymer, have been shown to activate caveolae-mediated endocytosis and pinocytosis, but not clatherin-mediated mechanisms in vitro (Tang et al., 2018). Therefore, active clatherin and caveolin mediated endocytic pathways may be utilized to promote particle uptake within the placenta; however use of these mechanisms may be particle dependent.

5.2. Apoptosis

Apoptosis is the controlled processes of programmed cell death. This tightly regulated process has been implicated in many disease states. Several placental in vitro studies, identify NP exposure as an initiating factor for reduced cellular viability, through apoptotic mechanisms, culminating in cytotoxicity. Exposure to nickel nanoparticles (Ni NP) resulted in reduced cellular viability associated with increased expression of the apoptosis mediators, caspase-3 and caspase-9 in HRT-8/Sveno cells (Li et al., 2022). In the same cell line, studies utilizing PS NPs also led to apoptotic activation as evidenced by an increased BAX/BCL ratio (Hu et al., 2022). Carboxylation of PS NPs also increased capsase-3 and cleaved capsase-3 in a 3 A-sub-E cells, a primary culture of term trophoblasts (Huang et al., 2015). Furthermore, primary trophoblast cells extracted from term human placentas, exposed to cerium dioxide (CeO₂) NPs, similarly induced apoptosis as assessed by reduced metabolic activity and a dose dependent upregulation in caspases 3/7 activity (Nedder et al., 2020). Overall, direct NP-cellular interactions induces the expression of apoptotic markers, resulting in dysregulated apoptosis and elevated cell death in vitro studies; however, these outcomes have yet to be established in vivo models.

5.3. Autophagy

Autophagy is the process by which cells degrade components and proteins, to conserve energy by recycling and reusing them for necessary processes. This mechanism is often employed under conditions of cellular stress. A translational approach of CeO₂ NP exposure described disrupted placental development in vivo, while mechanistic in vitro investigations identified activation of autophagy related pathways, as indicated by increased autophagosome and autolysosome activity in conjunction with elevated autophagy related substrates LC3, Beclin1, and P62 (Chen et al., 2022a,b,c). Similarly, expression of autophagy related substrates LC3 and Beclin1, were quantified following exposure of Cu NPs to pregnant Sprague Dawley rats, thus identifying autophagy activation (Kang et al., 2021). Therefore, it appears that NPs are able to induce autophagy in the placenta, which may result in placentation abnormalities and placental dysfunction.

5.4. Inflammation

Inflammation is the process by which the body defends itself from foreign invasion employing a variety of immune related cells. These cells act by releasing toxic chemicals to “kill” the invader or engulfing it to prevent replication and remove it from circulation. After the stimulus is removed, the immune response shifts toward repair and resolution. Toxicity can ensue in conditions where the balance between pro and anti-inflammatory mediators are disrupted. Several studies have investigated the induction of inflammation in the placenta following in vitro or in vivo exposure to various NPs.

In vitro assessments utilizing human placental choriocarcinoma JEG-3 cells, identified the upregulation of inflammatory genes CXCL6, ATF3, A20, and CCL2 after exposure to amine-modified or carboxylated PS NPs (Shen et al., 2022). In vivo exposure to silicone (Si) NPs via intravenous injection in ICR mice resulted in an increased infiltrations of CD4⁺ (immune) cells, induction of cytokines and inflammatory markers, (i.e., interleukin −1 B (IL-1β), IL-6, tumor necrosis factor (TNFα), and chemokine ligand 2 (CCL₂) indicative of NLRP2 inflammasome activation and inflammation in the placenta (Shirasuna et al., 2015). Si NPs also induced IL-1β secretion specifically in neutrophils, macrophages, and isolated placental cells (Shirasuna et al., 2015).

Intravenous injection of Ag NP into pregnant mice led to an increased expression of inflammatory markers IL6, IFNγ, p38mapk, Ap1 and MMP 9, resulting in systemic inflammation and increased expression of pro-inflammatory mediators (Chen et al., 2020). Exposure to PS NPs via intraperitoneal injection into pregnant mice led to increased infiltration of CD4⁺ immune cells in the placenta, reductions in pro-inflammatory mediator TNFα, and increased anti-inflammatory mediator IL-4 (Hu et al., 2021). Pulmonary intratracheal instillation of fine PM (PM_2.5) in rats resulted in inflammation, specifically elevated systemic IL-6, neutrophil infiltration, and adverse placental and perinatal outcomes (Liu et al., 2016). Pregnant C57BL/6 mice exposed to 15 nm Ag NP via nose-only inhalation resulted in increased placental expression of TNFα and IL-1β by infiltrating macrophages (Campagnolo et al., 2017). Sprague-Dawley rats in late stage of pregnancy exposed to nano-TiO₂ aerosols via whole body inhalation were found to have elevated plasma concentrations of IL-6 and IL-4, within 24 h of exposure (Stapleton et al., 2018). Furthermore, oral exposure to Cu NPs, including elevations in pro-inflammatory markers: IL-1β, COX2, and NF-K_β (Kang et al., 2021). It is important to note that systemic maternal effects, including inflammation, may indirectly impact the placenta due to the release of secondary mediators or impairments of integrated function (e.g., impaired blood flow delivery due to endothelial dysfunction associated with systemic inflammation) (Dugershaw et al., 2020). Overall, exposure NPs can disrupt immune regulation in the placenta and stimulate systemic markers of inflammation.

5.5. Oxidative stress

Oxidative stress is one of several mechanisms by which placental cells react to NPs in the local environment. Oxidative stress is defined as an imbalance between the generation of reactive oxygen species (ROS) and presence of antioxidants. ROS is often formed as an inflammatory reaction to damage foreign invaders. Excessive production of ROS is associated with cellular death and DNA damage, while antioxidants help to protect cells from injury associated with ROS.

Studies of placental-derived cells, demonstrate increased ROS production after NP exposure. Alterations in ROS production have been identified after exposure to urban PM_2.5 (Naav et al., 2020), PS NPs (Shen et al., 2022; Hu et al., 2022) and Ni NPs (Li et al., 2022). After Ni NP exposure, HTR8-Sveno cells had significant increases in ROS content accompanied by upregulation of malondialdehyde (MDA) content and reductions in the antioxidants superoxide dismutase (SOD) and CuZn/Mn-SOD; providing evidence that antioxidant depletion may play a role in the elevation of oxidative stress (Li et al., 2022). Reduced anti-inflammatory mediators in the form of H₂O₂ were identified after in vitro exposure to increasing concentrations of PM_2.5 (Naav et al., 2020).

There is also evidence that NP exposure in rats can result in increased ROS production (Manojlovic-Stojanoski et al., 2022; Chen et al., 2022a, b,c). TiO₂ NP exposure in pregnant Sprague Dawley rats, resulted in elevated placental ROS content (Chen et al., 2022a,b,c). Exposure to selenium (Se) NPs, corroborated these findings in pregnant Wistar rats (Manojlovic-Stojanoski et al., 2022). Specifically elevated levels of placental catalase, glutathione peroxidase, superoxide dismutase, and glutathione S-transferase, enzymes involved in the generation and metabolism of ROS, were identified after NP exposure (Manojlovic-Stojanoski et al., 2022). Therefore, it is evident that NP exposure can alter the balance between reactive oxygen species and antioxidants in cellular and animal models, but little is known about the mechanisms underlying these alterations.

5.6. Genotoxicity

Genotoxicity is the propensity for genetic mutation. Mutations can lead to genomic instability and the development of cancer. Exposures to genotoxic agents during pregnancy have adverse repercussion for both the maternal and fetal tissues. Investigations of genotoxic outcomes within the placenta after NP exposure are few. Therefore, it is imperative to determine the genomic consequences of NP exposure during pregnancy, and the consequences it can have on the fetus.

In vitro studies often evaluate genotoxicity via the comet assay. Placental derived BeWo cells produced a positive comet assay, or genotoxicity was identified, after exposure to oleic acid coated Fe₃O₄ and TiO₂ NPs (Cowie et al., 2015). Moreover, significantly high rates of DNA strand breaks were observed following exposure of 0.6–75 μg/cm² of TiO₂ to BeWo cells in vitro in the absence of cellular damage and cytotoxicity (Cowie et al., 2015). Studies utilizing HTR-8/Sveno cells identified that exposure to PM_2.5, consisting of a heterogeneous mixture of heavy metals and PAHs, significantly increased the percentage of DNA damage as evidenced by the comet assay (Qin et al., 2017). Mutagenicity tests conducted in rat hepatocytes provide evidence that Si NPs also induce genotoxicity; yet few mutagenicity investigations have occurred in placental tissues (Pinto et al., 2018).

Genotoxic effects of gestational NP exposure have been evaluated in maternal and fetal tissues after oral exposure to molybdenum nanoparticles revealing DNA damage in maternal and fetal tissues (Mohamed et al., 2020). Although placental tissues were not assessed, induction of DNA damage in the fetus following oral exposure is evidence that molybdenum NPs may have translocated and thus have the potential to cause genotoxicity in the placenta (Mohamed et al., 2020). Overall, NP exposure has been found to elicit genotoxicological outcomes, yet mechanistic evaluations and mutagenicity tests in the placenta are lacking.

5.7. Endocrine disruption

Endocrine disrupting chemicals (EDCs) interfere with the normal function of the endocrine system by acting as hormone mimetic or agonist to elicit a biological response. EDCs may also act as antagonists or inhibitors to reduce typical biological response. Furthermore, the placenta is also a highly metabolic organ that produces hormones involved in placental and fetal health. Placental hormones are essential to the regulation of placental metabolism, which is paramount to a successful pregnancy. Being that the placenta is an endocrine organ with an abundance of steroid receptors, it is especially susceptible to endocrine disruption.

Recent in vitro evidence supports the hypothesis that cellular internalization of NPs can disrupt endocrine function directly in the placenta by altering trophoblast cell differentiation and subsequently ability to secrete hormones. Studies conducted in fresh term primary trophoblast cells found that exposure to CeO₂ NPs affected the normal secretion of various hormones involved in pregnancy and produced from the placenta, including hCG, hPL, placental growth factor (PLGF), P₄, and E₂ (Nedder et al., 2020). At doses of 40 μg/mL and higher, there were significant reductions in placental hCG and hPL secretion and significant reductions in PLGF and E₂ production at 320 μg/mL (Nedder et al., 2020), indicating a significant endocrine disruption after high CeO₂ NPs exposure. Human placental choriocarcinoma JEG-3 cells exposed to PM₁ collected from urban Barcelona and rural Catalonia, Spain resulted in the inhibition of aromatase activity, an enzyme involved in steroid hormone biosynthetic pathways that facilitates the conversion of testosterone to estradiol (van Drooge et al., 2017). Protein Kinase A (PKA), an important protein involved in cellular transduction cascades and protein phosphorylation, was also inhibited in JEG-3 cells following exposure to PS NPs (Shen et al., 2022). Furthermore, greater inhibition of PKA was associated with positively charged (NH₂) modifications to the PS NPs (Shen et al., 2022). More recently, reductions in hsd17b levels, a gene involved is steroid hormone biosynthesis, were also identified following exposure to pristine and weathered PS and polyethylene (PE) NPs (Dusza et al., 2022). Collectively, these studies highlight the propensity for NPs to initiate endocrine disruption within the placenta.

In vivo investigations present evidence that gestational NP exposure can promote endocrine disruption. Oral exposure to TiO₂ NPs in pregnant Sprague Dawley rats led to the placental retention of maternal thyroid hormones thyroxine (T₄) and triiodothyronine (T₃) (Chen et al., 2022a). Accompanied with this retention was a significant decrease in the expression of thyroid hormone transport proteins, thyroxine-binding prealbumin (TTR), (thyroxine binding globulin (TBG), and albumin (ALB) (Chen et al., 2022b). These results are concerning given the ubiquitous use of TiO₂ NPs in conjunction with the importance of thyroid hormone access for successful maintenance of pregnancy and growth of the developing fetus (Chen et al., 2022c).

Disrupted placental metabolism has been reported following in vivo gestational exposure to PS NPs (Aghaei et al., 2022; Chen et al., 2022a,b, c). Using transcriptomic analyses, investigators were also able to identify metabolic disorders as evidenced by the upregulation of steroid metabolic processes, sterol and cholesterol homeostasis, lipid homeostasis, and increased expression of genes involved in these processes following PS NP exposure via drinking water in ICR mice (Chen et al., 2022a,b,c). Similarly, exposure to larger PS microplastics via drinking water in CD-1 mice led to a shift in biotin metabolism, lysine degradation, and glycolysis/gluconeogenesis (Aghaei et al., 2022). The placenta plays a major role in glucose, lipid, and steroid metabolic processes, which is highly regulated by placental lactogenic and somatogenic hormones; however, it is unclear if the alterations in the placentas metabolic function are directly related to endocrine disruption.

Placentation is heavily controlled by the endocrine function of the placenta. In vivo studies have identified that oral exposure to TiO₂ NPs early in pregnancy can alter the development of the placenta as evidenced by significant reductions in the labyrinth zone, increased area of the placental spongiotrophoblast, reductions in formation of the fetal vessel network, and reduction in the expression of genes involved in placental development (e.g., Hand 1, Esx1, Eomes, Hand 2) (Zhang et al., 2018). PM_2.5 was demonstrated to alter placentation by reducing cellular migration and invasion in an HTR-8 placental cells (Qin et al., 2017). Decrease trophoblast invasion and migration can have adverse effects on placentation and has been proposed as a mechanism of early pregnancy loss (Enkhmaa et al., 2014). Many studies have also documented adverse pregnancy outcomes and poor fetal health following maternal exposure to NPs. Fetal growth restriction and increased rates of fetal resorptions following in vivo exposure to Si (Yamashita et al., 2011), TiO₂ (Zhang et al., 2018; Stapleton et al., 2013), Ag (Campagnolo et al., 2017; Mozafari et al., 2020), and PS (Hu et al., 2021) NPs have been reported. Pregnancy is a strictly regulated process that involves the coordination of many hormones and endocrine processes. Disruptions to the endocrine processes in the placenta may provide mechanistic leads to assess poor pregnancy outcomes (e.g., increased rates of resorptions and reduced fetal growth).

6. Discussion

Pregnancy is a widely understudied life stage, wherein toxicities may not only be evident in the mother and fetus but may also lead to persistent health effects in the surviving offspring. The placenta is considered to be the primary barrier separating maternal and fetal circulations. More recently, the placenta has been identified as an endocrine organ, in addition to an anatomical barrier. Environmental exposures that effect placental health and function may have detrimental effects on maternal and fetal survival. NPs have been shown to translocate from the original origin of exposure to downstream tissues, including the placenta. NP interactions at the maternal-fetal interface have only recently been considered.

Transport across the placenta is biologically limited to protect the fetus. However, cellular distribution and uptake of NPs into the placenta have been documented (Ragusa et al., 2021; Fournier et al., 2020; Cary et al., 2023a,b; Campagnolo et al., 2017; D’Errico et al., 2022). Interestingly, NPs have also been shown to translocate other secondary barriers, such as the blood brain barrier (BBB) (Ye, Anguissola, O’Neill et al., 2015; Ye et al., 2013; Wang et al., 2008) and the blood testis barrier (BTB) (Kielbik et al., 2019), only few have provided concrete evidence of the mechanisms involved (Ye et al., 2013, 2015). Overall, uptake is likely to occur via active uptake associated with caveolin and clathrin-mediated endocytosis as prominent mechanisms (Kloet et al., 2015; Wang et al., 2020; Rattanapinyopituk et al., 2014; Tang et al., 2018; Ye et al., 2013, 2015). Although much work has been done to investigate the ability for NPs to cross a once thought impenetrable barrier, many questions still remain regarding the exact transport mechanisms being exploited within the placenta to facilitate NP entry, and potential translocation to the sensitive, developing fetus.

Perinatal nanomedicine has many applications including diagnostics, implantable devices, and medicinal delivery. NP utilized as vehicles within this frame may be developed with the intention to target maternal tissues only, placenta conditions, or fetal tissues after placental transfer. Therefore the consideration of NPs targeting the maternal-fetal interface for therapeutic is an attractive objective in perinatal medicine.

It is important to note that the concentrations of PM utilized to assess placental toxicities are considerably higher than realistic exposures (Bongaerts et al., 2023). The concentration and composition of NPs in indoor and outdoor air varies significantly by the geological location, time of day, and time of the year, although the relative fraction of particles remain consistent (Brzezina et al., 2020; Kundu and Stone, 2014; Liu et al., 2021). Aerosol concentrations of PM_2.5 in the Northeastern United States were identified as 46.7–779 μg/m³ within underground train stations, while the concentrations above the ground and outdoors were much lower, ranged from 10.0 to 24.1 μg/m³ (Luglio et al., 2021). Furthermore, analyses of personal monitoring devices concluded that pregnant women may be exposed to higher levels of PM_2.5, when compared to indoor and outdoor averages in the same areas (Schembari et al., 2013). These aerosol concentrations correlate to local placental tissue particle concentrations in a dose dependent manner. Concentrations of black carbon within the placenta (2.09 × 10⁴ or 0.95 × 10⁴ particles/mm³) were directly correlated to high residential black carbon exposure during pregnancy (1.70 μg/m³) or low residential exposures during pregnancy (0.96 μg/m³) (Bove et al., 2019). Currently, the analytical tools to identify real-world and translocated NPs are limited. NP blood concentrations are challenging to report as these particles do not form traditional metabolites. Methods of indirect measurements (i.e., ICP-MS) can only provide estimates of particle deposition, with no assessment of particle size, shape, or surface modifications. However, the disparity between real-world NP concentrations and laboratory doses must be considered.

As maternal physiology modifies during pregnancy to continually support fetal growth and development, the concentration of blood flow to the placenta increases during gestation. As particles translocate from of the original site of exposure (e.g., pulmonary or gastric system), it is important to recognize in laboratory studies that placental particle deposition may also increase exponentially over the timeline of gestation as blood flow to the placenta increases. Therefore in vitro and ex vivo studies representing early gestation may utilize a particle concentration that is lower than those mimicking late-term pregnancy. Furthermore, given the anatomical differences, tight cellular junctions, process of placentation, hormonal variations, and reduced cellular number at the chorionic villi, one could argue that the placental barrier of the human is more permeable than that of the rat or mouse (Stapleton, 2023). This must be a considerations when comparing studies between species.

As it pertains to endocrine disruption at the maternal-fetal interface due to NP exposure, plastic particles are of greatest concern. Plastics are often impregnated with plasticizing chemicals to promote characteristics of flexibility, rigidity, or color to the final products. Many of these plasticizing chemicals have been identified as EDCs. NPs also have the ability to adsorb chemicals to their surface, thus modifying their physiochemical properties and toxicity.

These speculations began with the discovery that EDCs can leach from microplastics in marine environments under normal conditions (Chen et al., 2019) and accumulate in aquatic life (Barboza et al., 2020). This has been demonstrated in environmental PM_2.5 collected in China (Qin et al., 2017) and Sweden (Naav et al., 2020), which identified detectable levels of metals and PAHs. Inhalation of polyamide microplastic particles has been shown to reduce circulating levels of 17-β estradiol in female rats during the estrus phase of their reproductive cycle (Cary et al., 2023). Therefore, it has been hypothesized that EDCs can be adsorbed to the surface of NPs or the plasticizing chemicals used in plastic development can leach into target tissues following cellular uptake (Ullah et al., 2022). To date, no studies have investigated the leaching of endocrine disrupting chemicals within the placenta following NP exposure, rendering the need for more research in this area. This lack of investigations make it difficult to determine the particle characteristics, and mechanisms leading to endocrine interference after NP exposure.

7. Conclusion

This review provides evidence of NP access to and accumulation within the placenta, identifying it as a tissue of interest and creating concern over the health of the developing fetus. The placenta is a vital endocrine organ in maintaining a successful pregnancy. In vivo and in vitro studies assessed in this review identify that NPs exploit a variety of active processes to promote cellular uptake, allowing NPs to not only enter the placenta, but also to traverse this organ to reach the fetal tissues. These interactions heavily rely on their physiochemical properties and chemical adsorption to promote trophoblast apoptosis, autophagy, inflammation, ROS, and genotoxicity. Together these outcomes promote cytotoxicity and placental dysfunction, impairing local and systemic endocrine function and gestational health. Unfortunately, there is a notable lack of mechanistic studies aimed at interrogating NP local NP interactions at the placenta affecting placental health and function. It is imperative that these mechanisms be understood to understand and minimize NP toxicity.

Abbreviations

NPs

Nanoparticles

HCG

Human chorionic gonadotropin

HPL

Human placental lactone/human chorionic somatotropin

PLGF

Placental Growth Factor

P₄

Progesterone

E₂

Estrogen

PGH

Placental growth hormone

ABC

ATP- binding cassette

SLC

Solute Carrier

EPA

Environmental Protection agency

EDCs

Endocrine disrupting chemicals

BPA

Bisphenol- A

PAH

Polycyclic Aromatic Hydrocarbons

MDD

Medical delivery device

NPs

Nanoparticles

PS

NPs Polystyrene NPs

Au

NPs Gold NPs

TiO₂

Titanium dioxide

Ag NPs

Silver NPs

PM

Particulate Matter

Si NP

Silica NPs

ZnO

Zinc Oxide

HPEC

Human Placental Endothelial Cells

CeO²

Cerium Dioxide

ROS

Reactive oxygen species

PKA

Protein kinase A

PGP

P glycoprotein

BCRP

Breast cancer resistance protein

MRP-1

Multidrug resistant protein 1. ??

GD

Gestational day

Il

Interleukin

TNFα

Tumor necrosis factor alpha

IFNγ

Interferon gamma

PA NPs

Pullulan acetate NPs

TH

Thyroid Hormone

T3

Triiodothyronine

T4

Thyroxine

TTR

Transthyretin

ALB

Albumin

MMP 9

Matrix metallopeptidase 9

Cu NPs

Copper NPs

NFKB

Nuclear Factor Kappa B

CCL2

Chemokine ligand 2

CXCL6

Chemokine ligand 6

ATF3

Activating Transcription factor 3

A20

Tumor Necrosis Factor α-Induced Protein 3

SOD

Superoxide dismutase

Fe₃O₄

Iron Oxide

GSH

Glutathione

GST

Glutathione-S-Transferase

Data availability

No data was used for the research described in the article.