Inhaled nanoparticles – human-made specks so minuscule they can’t be seen in conventional microscopes, found in thousands of common products – can cross a natural, protective barrier that normally protects fetuses, according to Rutgers University scientists studying factors that produce low-birth-weight babies.
The scientists reported in the medical journal Placenta they were able to track the movement of nanoparticles made of metal titanium dioxide through the bodies of pregnant rats.
After the nanoparticles were inhaled into the lungs of the rodents, some of them escaped this initial barrier. From there, the particles flowed through the placentas, which generally filter out foreign substances to protect the fetus.
“The particles are small and really hard to find,” said Phoebe Stapleton, an author and an assistant professor at Rutgers Ernest Mario School of Pharmacy and a faculty member at Rutgers Environmental and Occupational Health Sciences Institute. “But, using some specialized techniques, we found evidence that the particles can migrate from the lung to the placenta and possibly the fetal tissues after maternal exposure throughout pregnancy. The placenta does not act as a barrier to these particles. Nor do the lungs.”
Most nanoparticles are engineered, with few produced naturally. These particles are used in thousands of products, from sunscreens to pharmaceuticals to sports equipment. They are highly valued because they can enhance the effectiveness of drugs and produce sturdy-though-lightweight products.
Nanoparticles are so named because they are less than 100 nanometers wide, meaning they are tens of thousands of times smaller than the diameter of a single human hair. Despite their usefulness, nanoscale materials are poorly understood, with “very little known about the potential effects on human health and the environment,” according to the National Institute of Environmental Health Sciences.
During the experiment, scientists were surprised to also detect titanium dioxide in the “control” group of rats that hadn’t been given nanoparticles to inhale. It turns out the food given to the animals contained titanium dioxide. As a result, the researchers were able to observe the path the metal took through a rat’s body.
The research emerged from investigations into the causes of low birth weight in human infants. Newborns weighing less than 5.5 pounds can suffer adverse health effects as infants and throughout their lives.
According to Stapleton, one theory is mothers who give birth to babies with low birth weights may have inhaled harmful particulates. The resulting inflammation may affect bodily systems, such as blood flow in the uterus, that could inhibit growth of the fetus.
“Now that we know that the nanoparticles migrate – from the mother’s lungs to the placenta and fetal tissues—we can work on answering other questions,” Stapleton said. “This detail of transfer will help inform future studies of exposure during pregnancy, fetal health, and the developmental onset of disease.”
Other Rutgers authors on the paper included Brian Buckley and Cathleen Doherty at the Environmental and Occupational Health Sciences Institute, and Jeanine D’Errico and Jarett Reyes George at the Ernest Mario School of Pharmacy.
Since the thalidomide scandal in the early 1960s, it has become evident that the placenta does not provide a tight barrier, and that fetuses are exceptionally susceptible to potentially toxic substances compared to adults, due to the phases of rapid growth, range of developmental events and often irreversible nature of the induced changes .
The first indications of developmental toxicity of nanosized particles came from epidemiological studies, showing association of particulate matter (PM) exposure with adverse pregnancy outcomes such as low birth weight, preterm birth and preeclampsia [2,3,4].
Recently, it has been confirmed that environmental black carbon reaches the fetal side of the placenta in exposed pregnant women . With the advent of nanotechnology, novel NMs with unique properties can be industrially produced at large scales for application in food (reviewed in [6, 7]), cosmetics (reviewed in [7, 8]), medicine (reviewed in [9, 10]) and high-technology products (reviewed in [10, 11]).
These engineered NMs further contribute to human exposure to nanosized particles, and due to their high reactivity, pose additional health risks. However, investigations of the toxicological effects of engineered NMs, especially in vulnerable populations such as pregnant women and their unborn children, have lagged behind the development of new applications.
Importantly, to support safe-by-design and sustainable use of NMs, it is imperative to gain knowledge on the potential developmental toxicity of NMs and to understand the mechanisms underlying such toxicity.
In principle, NMs can affect fetal development through two fundamentally different pathways: a direct and an indirect pathway  (Fig. 1), that, however, are not mutually exclusive. Direct developmental toxicity may arise from particles in maternal blood that cross the placental barrier [13,14,15] and directly damage fetal tissues due to their high surface reactivity and propensity to induce inflammation [16,17,18], reactive oxygen species (ROS)  and hence oxidative stress reactions [20,21,22], among others.
Several FNMs are able to cross primary biological tissue barriers (e.g., lung [23, 24] and gastrointestinal (GI) tract [24, 25]) as well as the placenta [26,27,28,29], even if translocation is usually rather limited [30, 31]. Direct effects on embryonic and fetal tissues have been described for a variety of NMs in several in vitro studies as well as across species, including fish, chicken, and in vitro human stem cell (SC) models (reviewed in ). However, findings from organisms that lack a placenta or have a distinctly different placental structure might not directly correlate to the human condition.
The potential for NMs to affect fetal development by indirect pathways has been only marginally investigated and understood. Here, the concept is that NMs can interfere with fetal development in an indirect manner without being in direct contact with fetal tissue (Fig. 1). NMs deposited in primary maternal tissue barriers at the point of entry following oral, inhalation, dermal or intravenous (i.v.) exposure might induce oxidative stress and subsequently inflammation, leading to the release of inflammatory mediators and soluble signaling factors that can reach the placenta and fetus to induce potential toxic effects (maternal mediated developmental toxicity).
Alternatively, particles reaching the placenta can cause similar responses in the placental tissue, compromising placental function and inducing the release of placental signaling factors, which might impair embryo-fetal development (placental mediated developmental toxicity).
The aim of this review is to (i) collect the current knowledge base on the indirect developmental toxicity of NMs, (ii) compile and describe already known signaling pathways, (iii) propose novel candidate pathways and (iv) suggest directions of future research needs.
Risks and opportunities of NMs in pregnancy
For a proper risk assessment of NMs, a central aspect is to understand the exposure of pregnant women to NMs, including all relevant routes of exposure . Due to the use of NMs in many consumer, high-technology and biomedical products, pregnant women could be exposed to NMs via inhalation, absorption through damaged skin, ingestion or injection (Fig. 1) (reviewed in [34, 35]).
At production sites with applications of NMs, pregnant women can be exposed to NMs by inhalation, since the established protective legislation  does not come into action until the employer is made aware of the pregnancy, most often not until after the first 4–6 weeks.
Even then, NM exposure might continue, as the regulation does not specifically regulate NM relative to pregnancy [37, 38]. Ingestion of NMs used as food additives, in food packaging material or personal care products, constitutes another realistic route of exposure during pregnancy.
For example, the white food colorant E171 consists of particulate titanium dioxide (TiO2), with approximately 17–35% of the particles being within the nano-range (reviewed in [7, 39, 40]), and is present in toothpaste and various food products such as beverages, soups, cakes or candy in the European Union [41, 42].
In the United States, the dietary intake of TiO2 is estimated to be 1–2 mg/kg body weight per day for children, and 0.2–0.7 mg/kg body weight per day for other age groups [7, 42]. Dermal uptake of NMs present in personal care products, such as sunscreen, is expected to be minimal since the intact skin forms a tight barrier for NMs (reviewed in ).
Finally, particles may be directly injected into the body in case of medical application of NMs (reviewed in [9, 44, 45]), but currently, nanomedical therapies during pregnancy are still in the investigational stage. For instance, King et al. demonstrated the potential of iRGD (9-amino acid cyclic peptide: CRGDKGPDC)-decorated liposomes loaded with insulin-like growth factor (IGF)-2 for the treatment of fetal growth restriction in mice .
An oxytocin receptor coated liposomal carrier loaded with the tocolytic drug indomethacin substantially decreased preterm birth rates in mice . Nevertheless, before clinical use in pregnant women, not only the efficacy of the potential treatment in humans but also the safety of the NMs during pregnancy needs to be proven.
I.v. injection would make NMs readily systemically available. In contrast, only a low fraction of air and foodborne NMs would be expected to reach the systemic circulation and become bioavailable for maternal, placental and fetal tissues. Dermal exposure is expected to contribute very little to the systemic burden [27, 31].
Once NMs have reached the systemic circulation, they can distribute to maternal organs, including the placenta. As a highly perfused organ, the placenta is extensively exposed to circulating substances. Placental cells have been described to take up nanosized particles from the blood stream in experimental animals as well as the ex vivo human placenta perfusion model (e.g. [48,49,50,51]).
Studies on placental translocation of NMs in rodents, in the human ex vivo and in in vitro placenta models have shown that some types of NMs are retained in the maternal circulation while others can pass the placenta (reviewed in [26, 52]). Placental transfer appears to partially correlate withphysicochemical properties of NMs, in particular particle size .
However, other factors such as the gestational stage or combined physico-chemical properties can also affect placental translocation of NMs, making this process difficult to predict . As an example, a recent study demonstrated decreased fetal viability and growth, when 13 nm zinc oxide (ZnO) NPs were orally administered (7.2 mg/mouse) during organogenesis (gestational day (GD)7–16) in mice. However, when ZnO NP exposure occurred during the peri-implantation period (GD1-GD10) no fetal toxicity, but a slight change in placental weight, was observed .
For most routes of uptake (inhalation, ingestion and injection), gestational NM exposure has been associated with developmental toxicity for a variety of different NMs (extensively reviewed in [36, 55,56,57,58]). However, we have yet to identify the underlying mechanisms and which particle properties are of particular concern.
Organ systems of relevance for pathways of indirect developmental toxicity
For sure, the placenta should be a key focus in any mechanistic study on NM-mediated developmental toxicity due to its position at the interface between mother and fetus and its numerous essential functions during pregnancy. As a transient organ, the placenta starts forming after implantation of the conceptus in the uterine wall.
It consists of tissues of maternal (decidua) and fetal origin (amnion, chorion) [59, 60]. Anatomically, the maternal side of the placenta comprises the multinuclear syncytiotrophoblast (ST) layer, which is supported by a basal membrane, underlying cytotrophoblast cells, mesenchymal tissue and the microvascular endothelium of the fetal small blood vessels (Fig. 2).
This interface between the inner mucous membrane of the uterus (endometrium) and the fetus defines the degree to which maternally delivered substances reach the fetal tissue . During pregnancy, the placenta undergoes dramatic structural and functional changes to fulfill the evolving needs of the developing fetus.
During early pregnancy, the placental barrier is relatively thick (20–30 μm) and bilayered [62,63,64], but thins (2–4 μm) , becomes predominantly monolayered [62,63,64], and increases its surface area tremendously (to approx. 12 m2) towards the end of pregnancy to allow for efficient exchange of nutrients and gases required to sustain rapid fetal growth.
Placental damage, disease or impairment of its development or function are responsible for numerous pregnancy complications, including preeclampsia , miscarriage [63, 67] and intrauterine growth restriction [63, 67], and can likely impact offspring health later in life .
It should also be highlighted that the placenta is the most species-specific organ among mammals and shows remarkable differences in global structure, tissue layer organization, trophoblast cell types [69, 70] as well as molecular features . Therefore, translation from animal studies to the human situation should be done with caution, and the use of physiologically relevant placenta models is encouraged.
Also, maternal organs could mediate indirect developmental toxicity of NMs. Here, a focus should be on tissues at the port of entry that are in direct contact with particles such as the lung, the skin or the GI tract upon inhalation, dermal deposition or oral exposure, respectively.
Uptake and accumulation of NMs in these tissues could affect organ functions locally, but effects may spread to distant sites, including the placenta or the developing fetus, if particles interfere with essential signaling pathways. This concept is nicely exemplified in a recent study in mice, where systemic adverse effects (i.e. increased retention of activated leukocytes, secondary thrombocytosis, and pro-inflammatory responses in secondary organs) were observed only upon inhalation exposure to carbon NPs, but not after intra-arterial injection of an equivalent dose of particles to bypass the lung .
The mechanism(s) underlying the observed indirect systemic toxicity of carbon NPs appeared to involve inflammatory responses of the lung tissue . In addition to pro-inflammatory actions, NMs may also interfere with essential functions of the lung, skin or GI, such as gas exchange, digestion, nutrient uptake, metabolism or transport (Fig. 1). For instance, ZnO NPs can reduce iron and nutrient uptake and transfer at the intestinal barrier [73, 74].
reference link :https://particleandfibretoxicology.biomedcentral.com/articles/10.1186/s12989-020-00359-x
More information: J.N. D’Errico et al, Maternal, placental, and fetal distribution of titanium after repeated titanium dioxide nanoparticle inhalation through pregnancy, Placenta (2022). DOI: 10.1016/j.placenta.2022.03.008