The transfer of nanoparticles across the placental barrier, their potential embryotoxicity, and generational effects have been increasingly studied using mammalian models. Both metal and polymer nanoparticles exhibit distinct behaviors depending on their physicochemical properties, including size, surface charge, and composition. These factors influence their ability to cross biological barriers, interact with fetal tissues, and induce developmental or long-term health effects.
Placental transfer of nanoparticles is a critical area of investigation due to the potential for direct fetal exposure. Studies using rodent models have demonstrated that certain nanoparticles can traverse the placental barrier, though the extent varies by material and surface modification. For example, gold nanoparticles (5–50 nm) with neutral or negative surface charges show higher placental transfer rates compared to positively charged counterparts. Similarly, polystyrene nanoparticles (20–200 nm) have been detected in fetal tissues after maternal exposure, with smaller particles exhibiting greater translocation. The mechanism often involves passive diffusion or active transport via placental cells, though inflammatory responses may also disrupt barrier integrity, enhancing nanoparticle penetration.
Polymer nanoparticles, such as those made from poly(lactic-co-glycolic acid) (PLGA) or polyethylene glycol (PEG), demonstrate variable placental transfer depending on their surface functionalization. PEGylated nanoparticles, due to their stealth properties, exhibit prolonged circulation but may still cross the placenta in small quantities. In contrast, cationic polymer nanoparticles, such as those made from polyethylenimine (PEI), show higher accumulation in placental tissues but may induce localized toxicity, limiting fetal exposure.
Embryotoxicity of nanoparticles is influenced by their ability to induce oxidative stress, inflammation, or direct cellular damage. Metal nanoparticles, including silver (Ag) and titanium dioxide (TiO2), have been associated with developmental abnormalities in mammalian models. Prenatal exposure to Ag nanoparticles (10–50 nm) in mice resulted in reduced fetal weight and skeletal malformations at high doses (≥10 mg/kg). Similarly, TiO2 nanoparticles (20–100 nm) have been linked to neurodevelopmental delays and altered gene expression in offspring, likely due to maternal inflammatory responses rather than direct fetal nanoparticle accumulation.
Polymer nanoparticles generally exhibit lower acute embryotoxicity compared to metal nanoparticles but may still interfere with developmental processes. PLGA nanoparticles, widely used for drug delivery, show minimal toxicity at therapeutic doses but can induce oxidative stress at high concentrations. Dendrimers, such as polyamidoamine (PAMAM), have demonstrated dose-dependent embryotoxicity, with higher-generation dendrimers causing more significant developmental disruptions due to their strong interactions with cellular membranes.
Generational effects of nanoparticle exposure are an emerging concern, with evidence suggesting that prenatal exposure may lead to health consequences in subsequent generations. In rodent studies, maternal exposure to gold nanoparticles was associated with metabolic alterations in F1 offspring, including glucose intolerance and hepatic lipid accumulation. These effects were not always dose-dependent, indicating potential epigenetic modifications. Similarly, titanium dioxide nanoparticle exposure in pregnant rats led to behavioral abnormalities in F2 offspring, suggesting transgenerational epigenetic inheritance.
Polymer nanoparticles have shown fewer documented generational effects, though PEG-coated nanoparticles have been linked to subtle immune modulation in offspring. Long-term studies remain limited, but preliminary data suggest that chronic maternal exposure to certain polymer nanoparticles may alter offspring metabolism or immune function through indirect mechanisms, such as maternal immune activation.
Key factors influencing nanoparticle toxicity across generations include:
1. **Dose and duration**: Higher and repeated exposures increase the likelihood of placental transfer and fetal accumulation.
2. **Surface chemistry**: Charged or functionalized nanoparticles may exhibit greater biological interactions.
3. **Maternal health status**: Underlying inflammation or metabolic conditions can exacerbate nanoparticle effects.
Current research gaps include the long-term follow-up of offspring exposed prenatally to nanoparticles and the precise mechanisms of transgenerational epigenetic changes. Standardized dosing and exposure protocols are needed to improve comparability across studies.
In summary, metal and polymer nanoparticles can cross the placental barrier in mammalian models, with varying degrees of embryotoxicity and potential generational effects. While metal nanoparticles often induce more pronounced developmental toxicity due to oxidative stress, polymer nanoparticles may exert subtler but still significant effects, particularly with chronic exposure. Further research is essential to elucidate the full scope of developmental and transgenerational risks associated with nanomaterial exposure.