As the demand for plastic products has increased in recent years, global production of plastics has reached nearly 368 million metric tons, and improper disposal of plastic waste could lead to long-term exposure to environmental media (1). As one of the emerging pollutants, micro/nano-plastics (MNPs), with particle sizes of <5 mm and 1 μm, respectively (2, 3), whether derived directly from industrial, medical, and household products or from the larger plastics degradation, are currently receiving more worldwide attention. Another additional concern is that the ubiquity of microplastic contamination creates numerous ecological and environmental problems, as well as health issues for humans and other species. The three main ways of human intake of MNPs include the digestive tract, the respiratory tract, and skin contact (4). Many types of evidence have confirmed that humans continue to suffer from MNP pollution ever since the discovery by Thomson (5–11). Humans are getting exposed to MNPs through the inhalation of particles in the air and ingestion in diet, water, and dust (9, 12, 13). Moreover, it has been demonstrated that an infant is at a greater risk of MP exposure than an adult (14). At present, the accumulation of MNPs has been found in a variety of edible organisms, including in some foods taken daily and drinking water, as well as honey and tap water. In addition, mammals can take up more MNPs through biomagnification (15). At the same time, atmospheric particulate matter also contains a large amount of MNPs (11). The number of MPs inhaled through the respiratory tract can reach 553 per day, and this intake can irreversibly accumulate to 8.32 × 10³ (16). With the current global COVID-19 pandemic, wearing a mask has become an indispensable part of human daily life, while it is also found to be one of the sources of human intakes of MNPs (17–19). A recent survey found that a single mask releases more than 1 billion MNPs into the environment. MNPs have been found in human placenta, stools, lung tissue, human breastmilk, and blood, among others (8, 13, 20–24). This indicates that emerging environmental pollutants are having a long-term impact on human health and are becoming a global problem and concern.

Although the above evidence demonstrated the continuous exposure of MNPs to living species and human beings, the toxicological effects of MNPs still remain unknown (1, 4, 6, 25, 26). Based on medical ethics, we cannot impose experimental and environmental contaminants on humans. Consideration should be given to the extensive scientific exploration and observations that were obtained from in vitro studies (27) and animals, including mammals (28, 29).

Owing to their characteristics, terrestrial mammals were the common animal models for the exploration of the toxicological effects of MNPs. Most of the studies in this field have focused on mice and rats, and they have both made remarkable contributions to the progress of biomedicine (30, 31). Several studies have reported that exposure to MNPs could cause oxidative stress and inflammatory reactions (32–39). Nevertheless, other studies have found no effects of long-term low-dose exposure to MNPs on the mouse/rat models (40). These findings indicate that differences in plastic-type, exposure time, and concentration can result in differences in toxicological effects. The toxicological mechanism of MNPs still needs to be explored further (41).

We collected data to conduct a systematic analysis of the toxicological effects of MNPs on mouse/rat models and infer the toxicological effects on humans. Based on this study, we investigated the effects of different MNP types and exposure time on metabolism and reproduction in mice. We also explored the differences in reproductive toxicity of MPs in mice with different sexes. In addition, we performed a meta-analysis to investigate the effects of exposure to MNPs on glucose metabolism, reproduction, oxidative stress, and lipid metabolism in mice with sufficient data for predicting the impact of MNPs on human metabolism and reproduction. Our research supports the control of plastic pollution, including the reduction in plastic production, a gradual introduction of more environment-friendly and harmless alternatives, strict control of diet, and MNPs levels in the air. The present study aimed to provide a reference for speculating on the health effects of MNPs on humans; meanwhile, it also provides some evidence for conducting animal experiments.

It was reported that MPs were toxic to soil invertebrates and marine mammals (73, 74); however, a systematic summary of the toxicological effects of MNPs on terrestrial mammals, including mouse and rat, is lacking. Mouse and rat are the models and representatives of terrestrial mammals in the world. As the common and traditional model organisms in environmental toxicology, they have made outstanding contributions to the development of the disciplines of environmental toxicology and chemistry. Our study systematically summarizes the toxicological effects of MNPs size, concentration, and exposure duration on mice/rat models. There are a few studies on the toxicological effects of MNPs on rats, and the endpoints of rats were all <3 studies; therefore, the meta-analysis only analyzed those four studies on mice. The sensitivities of different strains of mice to MNPs exhibit significant differences, which are also one of the sources of heterogeneity.

All the included literature were divided into seven categories and 24 subcategories according to the different physiological functions and toxicity endpoints affected by MNPs, several of which, such as the nervous, reproduction, and gastrointestinal and metabolic systems, are worthy of attention. MNPs can be absorbed into the bloodstream through the gastrointestinal tract and deposited in the brains of mice, which causes neurotoxicity and attracts our attention. Our findings are consistent with the results of previous reviews (75). The toxicological effect of MNPs on the nervous system of mice was reflected in the fact that it can lead to brain PD-like neurodegeneration and behavioral and motor disorders and served as a potential risk factor for autism spectrum disorder (ASD). Studies have shown that toxicological effects were induced by MNPs to the mouse brain, which might lead to PD-like neurodegeneration mainly through the disturbance in energy metabolism in brain cells (59). MNPs can be transmitted at different nutritional levels through the food chain and eventually enter the body of mice, causing behavioral disorders (76). Another study examined the behavioral changes in mice of different ages through maternal exposure to MNPs, ultimately identifying MNPs as a potential contributor to ASD (77). Another study showed that the effect of PS-NPs on neurobehavior in rats was not statistically significant due to the limitations of small sample sizes and study design (78). There is an urgent need for more studies to further clarify the neurotoxic hazards and risks of MNP exposure.

Micro/nano-plastics have a significant impact on the reproductive function of mice. Reproductive toxicity mainly includes sperm deformities, testicular inflammation, and decreased testosterone levels in male mice (79) and ovarian inflammation and the quality reduction of oocytes in female mice (61). Several studies have further explored the transmission effect of exposing MNPs to the next generation (80–82). Moreover, they found that maternal exposure to MNPs in mice showed effects on the growth of offspring. Our results displayed that the male mice were more sensitive to the reproductive toxicity of MNPs. The toxicity of MNPs to the reproductive system of rats has mainly resulted in the deficiency of ovarian function in female mice (83). PS-MPs could cause apoptosis of ovarian granulosa cells through the NLRP3/Caspase-1 signaling pathway, and its mechanism might be related to oxidative stress (84). To date, most of the toxicological studies of MNPs on the reproductive system of mice have focused only on male mice; therefore, studies on the effects of the female reproductive system need to be carried out, and the lack of them has raised the issue of the need for a more reliable and extensive analysis.

Direct exposure of MNPs to the gastrointestinal system could result in an injury to the digestive tract tissue (33). Moreover, MNPs can accumulate in the intestinal tissue of mice, reduce intestinal mucus secretion, damage the intestinal barrier function, and change the diversity of intestinal flora (65). Therefore, it is necessary to explore the correlation between MNPs and the intestinal microflora, including the signaling pathways.

Exposure to MNPs poses a threat to the metabolic system of mouse/rat models. Among them, the biological endpoint of oxidative stress was the most concerning factor. Oxidative stress-related biological endpoints were assessed using relevant biomarkers, and the related signaling pathways were also identified (34). It also demonstrated that long-term MP exposure was a key risk factor that elicited oxidative stress in mice. MNPs could mediate the MAPK–Nrf2 signaling pathway by inducing oxidative stress, leading to the disruption of the blood–testis barrier in rats; thereby affecting the reproductive performance of rats (51). Another study found that MNPs could induce oxidative stress by activating the fibrosis-related Wnt/β-catenin signaling pathway to induce apoptosis in rat cardiomyocytes (71). MNPs induce reproductive toxicity, behavioral changes, and other adverse consequences through the oxidative stress cascade reaction and inflammatory reaction. At the same time, MNPs caused a disturbance in blood glucose and lipid metabolism in mice/rat models. The liver triglyceride and total cholesterol levels became reduced in mice treated with high concentrations of MPs, while no significant effects were observed in the low-concentration group (52). The disorder effect of blood glucose metabolism happened during >3 Class MPs exposure time. Normalized experiments for exploration of the exposure dose–/time–response relationships of MNPs should be established.

Micro/nano-plastics can enter the blood circulation of mice/rat models and become deposited in key tissues and target organs. During the deposition processes, they cause immune system disorders, blood toxicity, and organ damage, such as to the liver, kidneys, and lungs (36, 69, 85). It was found that MNPs could reduce the peripheral blood cell count by inhibiting the differentiation in bone marrow hematopoietic stem cells (67). MNPs increased the infiltration of natural killer cells and stimulation of cells into hepatocytes, and the expression of the inflammatory factor was upregulated. Another study found that MNPs cause oxidative stress, inflammation, and autophagy responses in renal cells; meanwhile, MNPs can accumulate in HK-2 cells and mouse kidneys (86). We found that 65.22% of the endpoints of visceral organ injury were significantly affected, which contributes to a few studies on this category with only 69 endpoints. Further studies are required to better understand the impact of MNPs on visceral organ injury.

Polystyrene and polyethylene are the most commonly used types and ingredients of MNP polymers in current experiments with mice and rat models. We explored the effects of different types of MPs on blood glucose and lipid metabolism in mice, and we observed that PS tended to have a more obvious effect on substance metabolism in mice than PE. It might be that there are fewer studies on the use of PE. It also found that functional amino acid- and carboxyl-group modified PS was more toxic than the original one, and the toxicity of PS-NH₂ was stronger than that of PS-COOH (65). The difference in toxicity might be due to the different surface charges in MNPs, and the charged PS-NH₂ and PS-COOH are more easily transported through the cellular membrane. Only one report tested the toxicity of rats by intragastric administration by using PP without observation of adverse reactions (87). More polymer types of MNPs should be explored and a comparison of their toxic effects should be made. In terms of human health, the most common polymers of MNPs that we are exposed to in daily life include not only PS and PE but also polyethylene terephthalate (9, 22). However, we are yet to find any animal tests and epidemiology reports on the effects of PS or PE on human health.

Size is considered to be a key factor affecting the toxicity of MNPs. Particles between 10 and 100 nm in size are more beneficial to pinocytosis and those between 4 and 10 nm in size can go through the membrane bilayer by direct penetration, which might be due to the large specific surface area of these small particles and induce a more efficient interaction with cells (88). NPs of 100 nm in size can penetrate the cell membrane more easily than MPs with larger sizes and accumulate in tissues and cells (74). Moreover, the surface mass ratio of NPs is larger than that of MPs, which enables NPs to more readily penetrate the lipid membrane directly (34). It was similar to our results, suggesting that NPs could damage the nervous and reproductive systems in mice easily (Figure 3). Similarly, the surface charge potential and the mass surface ratio of NPs make it easier to absorb free radicals. It has been reported that most MNPs with particle diameters smaller than 2.5–5 μm can enter the systemic circulation, thereby reaching multiple organs of the body and causing physiological damage (15).

The sizes of MPs detected in human feces, sputum, and breast milk were 20–800, 20–500, and 2–12 μm, respectively (10, 24, 89). Owing to the limitations in standard detection technology, it is currently difficult to detect all kinds of nanoscaled plastic particles in human samples. A comprehensive analysis of different biological tissue levels should be performed to discover the potential mechanism of NPs on organisms.

Exposure assessment should focus on the accumulation of MNPs into various tissues and organs and their ability to cross potential biological barriers to better detect the damage to health caused by MNPs (75). It has been reported that 488-nm PS–NPs can be deposited in the liver, intestine, and liver tissues of mice (90). Experiments performed on inhalation toxicity showed that 1-5 μm MPs could induce the infiltration of inflammatory cells in the lung tissue and the accumulation of bronchoalveolar macrophages (69). PS–NPs (80 nm) were found in multiple organs including the liver, kidney, and brain of the mice and caused damage to internal organs after their oral administration to mice (46). The size of MNPs is an important factor. A large particle is easy to accumulate in the digestive system and the respiratory system, whereas a small particle can enter the vital organs, including the brain, placenta, kidney, liver, and other organs, through biological barriers. The health risks of long-term exposure cannot be ignored.

The toxicity of MNPs also depends on the exposure concentration and dose. A study explored the toxicological effects of MNPs on mice through acute and repeated exposures, demonstrating that the lethal dose of MNPs to rats was higher than 2,000 mg/kg (50). Five groups of different concentrations ranging from 0 to 2,000 μgL⁻¹ were set up to explore the effects of MNPs on the reproductive system of rats in another study (91). It was found that MNPs caused oxidative stress, reducing the number of germ cells in rats and causing potential damage to the testis of rats in a dose-dependent manner. There is still a lack of data to explore the MNP concentration range of the effects on the reproductive system of mice/rat models, which is partly because of the different exposure and concentration calculation methods. Therefore, standardized exposure methods should be established for a better comparison between different studies.

Exposure time is also one of the important factors affecting the toxicity of MNPs. Reproductive toxicity depends on the concentration and exposure time, and a higher concentration and longer exposure time can lead to stronger toxicity. Studies using longer exposure times tend to adopt lower exposure concentrations, which might be due to the fact that only a few biological endpoints are affected by a longer exposure time. A previous study found that MPs affected the count and quality of sperm in mice by exposing them to 100 μg/L/day MPs for 180 days (35), which was much lower than the concentration of Lee's report, i.e., 2,000 mg/kg (50). The histopathologic evaluation revealed significant foreign body inflammation in the lung tissue in the 28-day repeated oral group (50). Therefore, a long-term repeated exposure to MNPs can lead to toxicological effects on mice/rat models.

The concentration and duration of exposure of mice to MNPs based on laboratory conditions are different from those of humans exposed to MNPs under the indicated conditions. A previous study suggested that a study that uses low-level prolonged exposures should be designed, which can get closer to real human exposures (92). Another study reported that commonly used plastic consumer goods, such as disposable food-grade nylon bags and hot low-density PE drink-cup liners, release NPs more than 10¹² L⁻¹ (93). On average, humans might ingest 0.1 to 5 g of MNPs per week through various routes of exposure (94). The concentrations and exposure times still need to be closer to the real levels. At present, the total daily intake of MNPs is mainly simulated by calculating the intake of water, food and inhaled air (16, 94). However, this method still has a few limitations because the MNPs released by the mask were not included in this model due to the COVID-19 pandemic.

Micro/nano-plastics (MNPs) can enter the organism in vivo through the digestive tract, the respiratory tract, and skin contact (16). Owing to the technical limitations and without standard methods used in the extraction, identification, and quantification of MNPs, it is hard to obtain the real concentration of MNPs in the environment and the exact exposure level of organisms. It has been reported that the concentration of MPs in the fecal samples of eight humans is 2 items/g faces (8). Another study extracted MPs from 50 healthy people and 52 patients with inflammatory bowel disease (IBD), and it was found that the average concentrations of MPs were 28 and 41.8 items/g faces, respectively (10). MNPs can be released into the air in all kinds of household products (11). In a study elaborating on the collection of sputum samples drawn from 22 patients with respiratory diseases, MPs were prevalent in all these sputum samples (89). A simulation of the ingestion of MNPs through respiration exhibited that an adult male could inhale 272 MPs/day (95). Plastic beads are added to many personal care products (96); therefore, the long-term use of such personal care products will lead to the exposure of MNPs in the human body.

At present, there is no clear evidence to support the impact of microplastics on human health. The survey found a positive correlation between fecal MPs and IBD status, suggesting that MP exposure may be related to the disease process or that IBD exacerbates the retention of MPs (10). The point is that more epidemiological studies are needed to fill in the gaps. Judging from the current detection of MNPs in human samples, the health risks of long-term exposure to humans are not optimistic.

The results of the present study also have some limitations. Ingestion and inhalation are the two main exposure patterns of human exposure to MNPs. Animal models ingest MNPs by gavage, and most of the doses of exposure were much higher than those ingested by human beings. In total, 5.1 × 10³ MNPs particles/day can be ingested by an adult from salt and 4.1 × 10⁴ items from drinking water, and the average annual inhalation intake of MNPs can reach 0.9 × 10⁴ to 7.9 × 10⁴ (15). The comparison between different exposure pathways and species is limited, and appropriate methods should be found for the actual amount of human MP exposure. From a medical ethics point of view, it is not possible to apply to or impose a chemical contaminant on a person to determine its actual dose. However, there is no clear method to assess the actual exposure of MPs.

The present study has systematically summarized the toxic effects of MNPs on mouse/rat models. The findings of the present study demonstrate that 52.78% of biological endpoints were found to be significantly affected by exposure to MNPs. These findings also provide insights into and directions for exploring the evidence and mechanisms of MNP effects on human health. However, further studies are required on the pathological mechanisms at the molecular level and the long-term and chronic effects of tissue accumulation. This review also aimed to guide future studies for establishing a standard MNP exposure model in rats and mice, and a further investigation of MNP exposure under comprehensive and real-world conditions, the potential toxic mechanisms, and the health effects.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

ZQ and NL were involved in the administrative support, conception, and design of the manuscript, data interpretation, reviewing, and revising the manuscript. WL was involved in the conception and design of the manuscript, collection and assembly of the data, data analysis, and drafting of the initial manuscript. BZ, QY, and XF were involved in the collection and assembly of data. TS, PG, and PaW were involved in drafting the initial manuscript. YB, BL, and PeW were involved in the critical review of the manuscript for important intellectual content. RL was involved in data analysis. All authors contributed to the article and approved the submitted version.