Microplastics and Health: A Review on Environmental Exposure, Toxicokinetics and Biological Effects

Abstract

Microplastics (MPs) are synthetic polymer particles that are generally less than 5 mm in size and have attracted heightened scrutiny due to their pervasive presence in the environment, along with their toxicological significance. Several research investigations documented its presence in humans as a profound finding in biological tissues and fluids crossing barriers, leading to oxidative and inflammatory pathways alterations associated with blood, placenta, cardiovascular, pulmonary, nephrotic, other systems, and their disorders. Given the ubiquitous utilization of microplastics across diverse sectors, it is imperative to systematically investigate and elucidate their potential toxicological effects on biological systems through rigorous and mechanistically informed research. This review will also provide the synthesis of recent mechanistic data on the toxicity that can be caused by MPs and will determine key gaps that impede efficient human health risk evaluation. A structured literature search was conducted via PubMed, Web of Science, and Scopus databases, mostly from the studies published between 2010 and 2026. The studies of exposure characteristics and biological effects were analyzed in vitro, in vivo, and in human biomonitoring, and the primary focus of the interventions includes oxidative stress, inflammation, apoptosis, hepatotoxicity, and metabolic malfunction. MPs possess various physicochemical properties, such as a low particle size, various shapes, surface area, polymer composition, and the presence of sorbed or intrinsic additives. When MPs are taken up by cells, they can induce oxidative stress via increasing ROS, eventually leading to high lipid peroxidation, mitochondrial malfunction, DNA fragmentation, and eventually cell death. MPs also cause pro-inflammatory cytokine responses, including TNF-α, IL-1β, and IL-6, altering the immune system and cell profile, leading to systemic inflammation. In aquatic and terrestrial organisms, these microplastics have a harmful impact on growth, reproduction, and behavior in a time- and dose-dependent manner. Under conditions of controlled exposure, the organ-specific toxicities that have been reported include hepatic, renal, neurological, reproductive, and cardiovascular systems. Although the fields of mechanistic knowledge are growing, there is still a substantial amount of uncertainty; there is a lack of characterization of the long-term effects of low-dose chronic exposure, the kinetics of bioaccumulation, biodegradation potential, and transgenerational effects. In addition, there are no standardized procedures for the characterization of MPs, nor the reporting of the distribution of size or exposure measurements, which limits the comparability of cross-studies and makes it difficult to assess risks quantitatively. The dynamics of interactions of MPs between co-adsorbed contaminants like heavy metals, polycyclic aromatic hydrocarbons, and endocrine-disrupting chemicals are also yet to be explored. Although all evidence available to date does indicate biologically plausible mechanisms of MP-induced toxicity, integrated research employing standardized analytical protocols, an environmentally relevant exposure model, and human epidemiological data is required to ensure that laboratory results are translated into evidence-based public health and regulatory actions. This review offers an in-depth analysis of the existing molecular understanding of MP-induced toxicity, demonstrates organism-level impacts throughout species, and establishes vital fields for future studies. In order to develop competent guidelines to minimize MP exposure and its adverse health effects, it is crucial to cover these gaps via research that incorporates toxicology and environmental science.

1. Introduction

Global plastic production has increased exponentially from about 1.5 million tons in the 1950s to over 400 million tons a year in recent years, leading to unprecedented environmental issues, particularly in relation to the persistence and fragmentation of plastics into micro- and nanoscale particles [1,2]. Due to their ubiquitous presence and poorly known effects on biological systems, microplastic (MP) particles (less than 5 mm) emerge as environmental pollutants and can be classified as primary or secondary. Primary MPs are produced for specific applications, such as industrial abrasives, drug delivery systems, and exfoliants, while secondary macroparticles are produced when large plastic debris is broken down into small pieces via different activities such as microbiological, photolysis, mechanical abrasion, and thermo-oxidative weathering [3,4]. Microplastics often travel, to a large extent, due to their small size, hydrophobic nature, and physicochemical stability, accumulating in a range of environmental compartments such as far-off mountain snow caps to deep-sea sediments [5]. Microplastics are often studied to discover the impact they have on humans, as their presence has been found in human edible plants, dairy products, potable water, and fish, and poses exposure and toxicological threats to biological organs such as the liver, lungs, blood, placenta, and gastrointestinal tract. Humans are exposed to MPs mostly by food and inhalation, while skin contact may be important in work-related situations [6,7,8]. Ingestion results from consuming tainted food and drink, such as processed foods, shellfish, fruits, vegetables, table salt, and drinking water. Airborne macroparticles, particularly from synthetic fibers in the textile industry, pose a serious threat as their inhalation results in the internalization of these macroparticles via passing through epithelial barriers into the bloodstream, thus passing to distant organs [9].

Microplastics also induce oxidative stress, immunological dysregulation, endocrine disruption, reproductive toxicity, neurotoxicity, and even transgenerational epigenetic changes, according to an expanding corpus of in vitro and in vivo research [10,11,12,13,14]. The production of reactive oxygen species (ROS), either directly as a result of transition metals or indirectly through mitochondrial malfunction or inflammatory cell activation, is a crucial initial event. The resulting oxidative stress can cause apoptosis or necrosis, thus damaging the lipids and nucleic acids, and causing changes in cellular redox equilibrium. Along with oxidative stress, several pro-inflammatory reactions activate various transcription factors like NF-κB and AP-1, and upregulate cytokines, including IL-1β, IL-6, and TNF-α. Inflammasome activation, epithelial barrier failure, and macrophage polarization are important characteristics of MP-induced immunotoxicity [15]. Prolonged MP exposure has also been linked to immunological fatigue, T-cell activation, and decreased antigen presentation according to specific studies [16]. Furthermore, MPs could impact endocrine homeostasis by leaking plasticizers and monomers that contain substances with estrogenic, anti-androgenic, and thyroid-disrupting characteristics, including phthalates, bisphenol A (BPA), and polybrominated diphenyl ethers (PBDEs) [17]. For both aquatic and mammalian models, these chemicals have been shown to interrupt the hypothalamic–pituitary–gonadal axis, interact with the receptors for nuclear hormones (including ER, AR, and TR), and affect steroid production, reproductive development, and libido [18]. Following exposure to these macroparticles, zebrafish, rats, and neuronal cell cultures have demonstrated behavioral abnormalities, altered locomotion, neurotransmitter dysregulation, microglial activation, and neuroinflammation, raising concerns about the neurotoxic effects of microplastics [19]. These effects are thought to result from both indirect inflammatory cascades and direct neuronal uptake. Oxidative damage to the dopaminergic and cholinergic systems, along with epigenetic alterations in brain tissues, has also been reported. Experimental studies indicate that microplastics can trigger molecular and cellular responses, influencing multiple biological pathways and modulating inflammatory and oxidative stress pathways. These changes may result in maternal–fetal transfer of microplastics, posing potential risk to developing embryos, postpartum vascularization, and neonatal immunity [20,21]. Toxic effects are not limited to laboratory settings; ecotoxicological investigations across diverse taxa—ranging from phytoplankton and crustaceans to earthworms, amphibians, birds, and mammals—have confirmed that microplastics can activate biological pathways associated with developmental delays, growth inhibition, reproductive suppression, altered feeding behavior, and histopathological damage [22].

Microplastics (MPs) are consumed by filter-feeding and deposit-feeding species, often leading to stomach obstruction, energy loss, and reduced food absorption. At higher trophic levels, MPs have been shown to accumulate in organs such as the kidneys, muscles, and brain, demonstrating their ability to bioaccumulate across the food chain [23]. Ingestion of these particles can also result in gut blockage, reduced energy levels, and impaired nutrient assimilation [24]. At advanced trophic levels, microplastics can translocate and accumulate in the liver, muscles, and brain tissues, ultimately contributing to bioaccumulation throughout the food web [25]. In addition, microplastics can interact synergistically with other environmental factors. They readily absorb heavy metals such as lead, cadmium, and mercury, as well as polycyclic aromatic hydrocarbons (PAHs), pharmaceuticals, and microbial communities (biofilms) [26]. Several studies have demonstrated that it causes hepatotoxicity and neurotoxicity in rodents, along with genotoxic effects in aquatic organisms [27].

Despite numerous studies and reviews examining and reviews the environmental distribution, ecological effects, and overall toxicological impacts of microplastics (MPs), there remains a critical need to better understand the microplastics-induced toxicity. Current investigations are limited by inadequate exposure models, poor comparability of biological endpoints, and inconsistent particle characterization. Relatively few studies have incorporated mechanistic evidence linking environmental exposure to MPs with inflammation, oxidative stress, apoptotic pathways, and metabolic disruptions within a unified ecological framework. Moreover, little focus has been given to dose–response relationships, the relevance of exposure to human health, and the potential role of MPs in metabolic disorders such as non-alcoholic fatty liver disease (NAFLD) [28,29]. In addition, the long-term consequences of chronic, low-dose exposure, especially among vulnerable populations such as infants, pregnant women, and immunocompromised individuals, remain poorly understood. Similarly, there is a lack of detailed information on the pharmacokinetics, biotransformation processes, and clearance of MPs following internalization, which hinders comprehensive risk assessment. This article compiles current knowledge on the potential hazards of microplastics by describing their primary routes of entry into the body, elucidating mechanisms underlying oxidative stress, inflammation, endocrine disruption, and neurotoxicity, and examining their impacts across different taxonomic groups of microorganisms. It also discusses the role of MPs as chemical vectors, analytical tools used to assess toxicity, and emerging approaches such as omics-based analyses and advanced imaging techniques. The primary objective of this review is to synthesize existing experimental and biomonitoring data to better understand the molecular pathways of MP-induced toxicity and evaluate cell-level effects across aquatic, terrestrial, and mammalian systems. This review provides a more comprehensive and translational perspective compared to previous studies by integrating mechanistic insights with realistic exposure scenarios. Furthermore, it highlights significant knowledge gaps and identifies priority areas for future research, aiming to support the development of evidence-based strategies for reducing plastic exposure and safeguarding human health. It also outlines underexplored research areas to guide future investigations, risk assessment, and policy formulation.

2. Routes of Exposure and Toxicokinetics

Microplastics (MPs) have permeated virtually every environmental compartment—air, water, soil, and biota resulting in multiple potential exposure pathways for humans and animals [30]. The primary routes through which MPs enter biological systems include ingestion, inhalation, and dermal absorption, with ingestion and inhalation being the most dominant and concerning due to their potential for systemic distribution and organ-level bioaccumulation [31]. Advances in analytical methods have enabled the detection of microplastics in human biological samples, providing direct evidence of systemic exposure. Raman micro spectroscopy, as used by Ragusa et al., identified pigmented polypropylene fragments in human placental tissue, indicating the maternal–fetal interface [32]. Similarly, Leslie et al. reported the presence of polymer particles, such as polyethylene terephthalate and polystyrene, in human blood samples, suggesting systemic circulation [33]. More recently, Jenner et al. found microplastic fibers and fragments in human lung tissue obtained from surgical resections, confirming inhalation as a probable exposure route [34]. Although these studies demonstrate the presence of MPs in human tissues, they do not establish causality with clinical disease outcomes and analytical sensitivity.

A comprehensive assessment of absorption, distribution, metabolism (biotransformation) and excretion (ADME) is essential, as the toxicokinetics of microplastics and nanoplastics are governed by particle size, surface chemistry, polymer composition, aggregation state, and interactions with biological matrices. Therefore, particle-specific characteristics and biological transport pathways must be integrated into a mechanistic toxicokinetic framework.

2.1. Ingestion

Ingestion is one of the well-documented routes of microplastic exposure in humans. Numerous dietary sources, including seafood, honey, salt, fruits and vegetables, have been reported to contain MPs. Filter-feeding organisms such as mussels, oysters, and crustaceans can accumulate microplastics, acting as both bioindicators and vectors for trophic transfer to humans and higher trophic levels. Several studies have also reported the presence of MPs in commonly consumed crops such as lettuce, carrots, and tomatoes, attributed to agricultural practices such as plastic mulching, biosolid application, and wastewater irrigation [35,36]. In addition, processed foods and drinking water (both tap and bottled) have been identified as significant sources of exposure. A recent meta-analysis estimated that humans may invest approximately 39,000 and 52,000 MPs annually through food and beverages alone [37]. The detection of MPs in human feces further confirms gastrointestinal exposure.

Ingested microplastics may alter gut microbiota, induce local inflammatory responses, and interact with gastrointestinal epithelial cells. Through mechanisms such as endocytosis, paracellular transport, or M-cell-mediated translocation in Peyer’s patches, particles, particularly nanoscale plastics, can cross intestinal barriers following internalization [38]. Smaller microplastics (<10 µm) and nano plastics exhibit higher translocation potential due to their size and increased surface area to volume ratio, which enhances absorption efficiency. Experimental studies suggest that systemic uptake of microplastics is approximately 1% of the administered dose, whereas nanoplastics show translocation rates ranging from 0.2% to 5% in rodent models. These rates are influenced by factors such as surface charge, inflammatory status, paracellular permeability, and other physiological and pathological conditions [39,40]. Once internalized, these particles may enter systemic circulation and accumulate in organs such as the liver, spleen, kidneys, and brain [27].

2.2. Inhalation

Inhalation of airborne microplastics (MPs) has emerged as a well-recognized and increasingly significant exposure route, particularly in indoor and urban environments. Microplastics (MPs) can enter the human body through multiple exposure pathways, including ingestion, inhalation, dermal contact, and vertical transfer, as illustrated in Figure 1. The primary sources of inhalable MPs are synthetic materials found in textiles, home furnishings, rugs, and suspended household dust [41,42]. Compared to outdoor environments, indoor air often contains significantly higher concentrations of microplastic fragments, with exposure risk being greatest in confined and poorly ventilated spaces [43]. Airborne MPs vary in size, ranging from visible fibers to ultrafine particles capable of deeply penetrating the pulmonary alveoli. Epidemiological studies indicate that workers in industries such as waste recycling, thermoplastic manufacturing, and textiles are particularly susceptible due to prolonged exposure to polymer dust [44]. Occupational exposure has been associated with bronchitis, respiratory symptoms, and interstitial lung disease, commonly referred to as “flock worker’s lung” [45]. Based on their aerodynamic dimensions, MPs can deposit throughout the respiratory tract particles smaller than 2.5 µm (PM 2.5), can evade mucociliary clearance, and reach alveolar spaces [46,47]. Particles larger than 10 µ tend to deposit in bronchiolar regions through sedimentation mechanisms with increasing deposition efficiency and enhanced diffusivity. Furthermore, they may induce oxidative stress, localized inflammation, and potential translocation into the bloodstream via alveolar capillaries [48]. Recent studies have demonstrated systemic migration through the respiratory pathway by detecting small plastic fragments in human lung tissue obtained from biopsy and postmortem analyses [49]. Deposition is also influenced by particle morphology; high aspect-ratio fibers tend to align with airflow, enabling deeper penetration into the lungs compared to spherical particles of similar mass.

2.3. Dermal Exposure

Dermal exposure is comparatively less studied but may occur through contact with contaminated soil, water or personal care products having microbeads or exfoliating agents. Skin penetration of microplastics is generally considered limited due to the protective barrier provided by the stratum corneum [50]. However, under certain conditions, such as prolonged exposure, compromised skin integrity (e.g., eczema or wounds), or the presence of nano plastics, the potential for percutaneous absorption may increase [51]. Dermal exposure may also be relevant in occupational settings where workers handle polymer-rich dust or liquids. Additionally, MPs present in cosmetics, shampoos, and soaps may persist on the skin or accumulate in hair follicles or sweat ducts, although conclusive evidence of deep dermal penetration remains limited [52].

2.4. Vertical and Transgenerational Exposure

Recent evidence raises concerns about fetal exposure during critical developmental stages, suggesting that MPs, particularly nano plastics, may cross the placental barrier. Studies have identified plastic particles in human placental tissue, amniotic fluid, and even meconium, indicating in utero exposure [53,54,55,56]. Such early exposure may have long-term consequences mediated through epigenetic mechanisms, potentially affecting neurobehavioral development, metabolic programming, and immune function. Animal studies have shown that maternal exposure to MPs can lead to transgenerational effects, including reduced fertility, altered organ development, and abnormal behavioral patterns in offspring [57,58]. These findings highlighted the significance of incorporating perinatal and reproductive risk assessment frameworks.

2.5. Indirect and Combined Exposure Routes

In real-world conditions, humans and animals are exposed to MPs through multiple simultaneous pathways, often in combination with other environmental contaminants such as heavy metals, polyaromatic hydrocarbons (PAHs), and persistent organic pollutants (POPs) [59,60]. MPs can adsorb and concentrate these toxic substances on their surfaces and subsequently release them under physiological conditions [61]. This co-exposure mechanism may enhance the bioavailability and toxicity of associated chemicals. The effect is particularly significant in the gastrointestinal tract, where acidic pH and enzyme activity can promote desorption. Moreover, interactions between MPs and the gut, skin, or respiratory microbiome may influence human health by altering microbial composition, metabolic functions, and host immune responses [62]. MP-induced dysbiosis has been associated with increased intestinal permeability, systemic inflammation, and potentially neuroimmune disorders [63].

2.6. Distribution, Physicochemical Modifications, Metabolism and Biotransformation of Microplastics and Nanoplastics

Microplastics (MPs) and nanoplastics (NPs) are systemically distributed throughout the body depending on particle size, surface chemistry, protein corona formation, and organ-specific phagocytic activity [64]. Unlike dissolved xenobiotics, these materials behave as colloidal particulates, and their biodistribution is governed by vascular dynamics and immune recognition. Plasma proteins such as albumin, fibrinogen, immunoglobulins, complement factors, and apolipoproteins rapidly adsorb onto NPs in the bloodstream, forming a biomolecular corona. This corona defines the biological identity of the particle and influences opsonization, endothelial interactions and cellular uptake [65]. Particles smaller than 100 nm tend to persist in circulation for several hours due to inefficient clearance, whereas larger particles (>500 nm) are rapidly recognized by the mononuclear phagocyte system and cleared within 24 h [66]. Liver Kupffer cells and splenic macrophages play a major role in the clearance of opsonized particles as part of the reticuloendothelial system.

Biodistribution studies under controlled exposure conditions all show dominance accumulation in the liver, with approximately 40–60% of MPs and 50–70% of NPs localized in hepatic tissue [67]. This reflects high hepatic blood flow and an abundant macrophage population. The spleen typically accumulates 10–15% of MPs and 15–25% of NPs due to its filtration function. Renal accumulation is comparatively low (5–10% for MPs and up to 15% for NPs), although nanoscale particles may pass through glomerular structures depending on size and surface charge [68]. Brain accumulation of MPs is minimal (<1%); however, NPs smaller than approx. ~50 nm can cross the blood–brain barrier, with reported penetration rates of 5–10% in animal models [68]. Pulmonary retention contributes 10–30% of the burden, particularly under inhalation exposure. Smaller particles exhibit wider systemic distribution due to enhanced endothelial penetration and less phagocytic clearance. Physicochemical transformations significantly influence these kinetics. The composition of the protein corona varies with the biological fluid and evolves dynamically through competitive protein exchange, thereby altering immune recognition, complement activation, and cellular internalization [69]. Environmental aging processes, such as ultraviolet exposure and oxidative weathering, introduce functional groups (e.g., carbonyls and hydroxyl groups) that enhance hydrophilicity and modify electrostatic properties. These changes enhance protein absorption, cellular uptake, and oxidative stress responses [70]. Weathered MPs have been shown to induce greater inflammation than pristine particles, highlighting the importance of environmental transformation prior to biological exposure.

The polymer backbone undergoes minimal metabolic modification. High-molecular-weight polymers such as polyethylene, polypropylene, polystyrene, and polyethylene terephthalate are resistant to enzymatic degradation in mammalian systems [71]. Cytochrome P450 enzymes are unable to cleave polymer chains, and lysosomal conditions result in only minor surface alterations without significant degradation. Consequently, particle fate is largely determined by persistence rather than metabolic clearance [72]. However, embedded chemical additives represent an additional exposure pathway. Under physiological conditions, plasticizers, bisphenols and flame retardants may leach from particles, with rates influenced by polymer composition, surface area, temperature and pH. Once released, these additives undergo conventional absorption, distribution, metabolism, and excretion processes and may exert endocrine or toxic effects independently of the particle matrix [73]. Thus, systemic burden reflects a dual toxicokinetic profile comprising persistent particle accumulation and soluble additive exposure.

2.7. Bioaccumulation Kinetics, Excretion, Elimination Pathways and Mechanistic Implications of Toxicokinetics

Systemic absorption, tissue retention, and clearance efficacy strongly influence the bioaccumulation kinetics of MPs and NPs. For MPs in the 1–10 µm size range, systemic bioaccumulation is generally limited due to poor gastrointestinal absorption, typically estimated at 0.1–1.0% of the administered dose in experimental systems [74]. Most ingested MPs are excreted unchanged in feces, with only a small fraction translocating across intestinal barriers via paracellular pathways or uptake by specialized M cells in gut-associated lymphoid tissues. Retained MPs are primarily localized in the liver and intestinal immune compartments following phagocytic uptake, resulting in relatively low long-term systemic accumulation under typical exposure conditions.

In contrast, NPs (<100 nm) exhibit significantly greater bioaccumulation due to higher absorption efficiency and slower systemic clearance. Gastrointestinal uptake ranges from approximately 0.5–5% depending on particle characterization such as size, surface charge, and coating. Inhalation uptake is also higher for NPs (approximately 1–2%) compared to MPs (<0.5%). NPs have a plasma half-life of approximately 6–12 h [75] and can distribute to secondary organs once following systemic circulation. Sub-chronic rodent studies have reported retention for up to 30 days following repeated exposure, with particularly high accumulation in the liver [76,77]. The spleen also shows moderate accumulation due to its immune surveillance role. Notably, NPs smaller than ~50 nm have demonstrated measurable penetration across the blood–brain barrier, whereas MPs show negligible brain uptake. Continuous low-dose exposure to NPs may result in progressive tissue accumulation due to slow elimination rates, even at low absorption fractions.

Elimination pathways differ markedly between MPs and NPs. MPs are primarily excreted via feces, although excretion efficiency decreases for particles smaller than 1 µm due to increased tissue uptake [78]. Renal clearance is negligible for most NPs because the glomerular filtration threshold (~6–8 nm) excludes larger particles; only very small and well-dispersed NPs (~5–8 nm) can be excreted via urine [78]. Hepatobiliary excretion has been observed for certain NPs following hepatic uptake, facilitated by protein-mediated transport into bile canaliculi. However, this pathway is variable and depends on particle size, surface characteristics, and liver transport capacity [78].

These toxicokinetic differences have important mechanistic implications. Accumulation of MPs and especially NPs accumulation in the liver activates macrophages and Kupffer cells, triggering inflammasome pathways such as NLRP3, and promoting the release of pro-inflammatory cytokines (IL-1β and TNF-α) [79]. Increased NP burden in reticuloendothelial organs is associated with elevated levels of systemic inflammatory markers. Persistent endo lysosomal accumulation may destabilize membranes, generate reactive oxygen species, and activate intrinsic apo apoptotic signaling pathways. NPs are known to induce stronger apoptotic responses at lower concentrations compared to MPs [79]. The relative contribution of different exposure routes of microplastics, along with their major sources, is summarized in Figure 2.

Significant uncertainties remain in extrapolating experimental findings to human exposure scenarios. Estimated human exposure to MPs through diet and drinking water ranges from tens of thousands to millions of particles annually, corresponding to microgram-scale daily intake [80]. Airborne exposure contributes additional inhalation doses, particularly in indoor environments rich in synthetic fibers [81,82]. However, internal dose estimates remain uncertain due to limited human biomonitoring data. Detection of MPs in human blood, placenta and lung tissue confirms systemic exposure, but quantitative relationships between environmental exposure and tissue burden are not yet well established. Furthermore, experimental studies often employ higher concentrations to elicit observable biological responses with short timeframes, necessitating caution when extrapolating dose–response relationships to real-world exposure conditions.

3. Mechanisms of Toxicity

Microplastics (MPs), particularly at the nanoscale level, exert toxicological effects through multiple interconnected mechanisms, including chemical and biochemical alterations at cellular and systemic levels, as well as physical disruption of cell structures [83]. Key processes include oxidative stress, inflammation, endocrine disruption, genotoxicity, and metabolic dysregulation. Biological activity and distribution depend on particle size, morphology, surface chemistry, polymer type, and associated contaminants [84].

Experimental studies demonstrate that polystyrene nanoplastics increase reactive oxygen species (ROS) production and pro-inflammatory cytokine (TNF-α and IL-1β) in retinal and epithelial tissues, indicating activation of oxidative stress and inflammatory pathways. These effects are dose-dependent, with similar findings reported in mouse ocular surface models. Polyethylene glycol (PEG)-based microplastics have also been shown to induce dose-dependent bioaccumulation and histopathological alterations in liver and gut tissues in aquatic models such as zebrafish.

3.1. Oxidative Stress and Redox Imbalance

Oxidative stress is one of the most frequently reported mechanisms of MP-induced toxicity across multiple organ systems. Internalized MPs or their surface-bound additives promote excessive generation of reactive oxygen species (ROS), including superoxide anions (O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radicals (OH^•), overwhelming antioxidant defense systems [85,86]. Upon cellular uptake, particularly for nanoplastics (<100 nm), particles interact with mitochondrial membranes and redox-sensitive signaling pathways, leading to lipid peroxidation, protein carbonylation, and nucleic acid damage, thereby compromising cellular integrity [87,88]. MPs and NPs may also disrupt the electron transport chain, impair ATP synthesis, and contribute to the self-replicating oxidative cycle. Additionally, oxidative stress activates signaling pathways associated with inflammation and apoptosis [16,89].

3.2. Inflammation and Cytokine Storm

MP exposure induces strong inflammatory responses. Pattern recognition receptors (PRRs), including Toll-like receptors (TLR2 and TLR4), recognize MPs as pathogen-associated molecular patterns (PAMPs), activating signaling pathways such as NF-kB and MAPK (ERK, JNK, p38) [16,90]. This activation leads to upregulation of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and chemokines (MCP-1, CXCL1) [91]. MPs also promote activation of inflammasomes, particularly NLRP3, which facilitates caspase-1 activation and subsequent release of IL-1β and IL-18 [92,93]. In vitro studies using epithelial, hepatic, immune, and intestinal cell models (A549, HepG2, Caco-2, THP-1) demonstrate increased cytokine production following exposure to polystyrene, polyethylene and polypropylene particles [94,95]. Significantly inflammatory responses are observed at concentrations as low as 10 µg/mL) for NPs. In vivo rodent studies further confirm increased hepatic cytokine levels and Kupffer cell activation following oral MP exposure. Chronic low-grade inflammation induced by MPs is associated with metabolic disorders, cardiovascular disease, neurodegeneration, fibrosis, and carcinogenesis [96,97,98,99,100,101,102].

3.3. Apoptosis and Programmed Cell Death

MPs induce apoptosis primarily through the intrinsic mitochondrial pathway. Excess ROS generation leads to mitochondrial damage and release of cytochrome c, which forms an apoptosome with Apaf-1 and caspase-9, ultimately activating executioner caspases (caspase-3 and -7) [102,103]. Affected cell types include hepatocytes, neurons, and reproductive cells, with observed alterations in Bax/Bcl-2 ratios and mitochondrial membrane potential. Apoptotic effects are typically observed at concentrations of >10–50 µg/mL for MPs and at lower concentrations (1–5 µg/mL) for NPs, reflecting higher cellular uptake and toxicity of nanoscale particles [104,105]. Such size-dependent potency indicates enhanced cellular uptake, increased lysosomal localization, and greater oxidative stress generation by nanoscale particles. Repeated oral exposure to MPs in rodent models (typically 1–5 mg/kg/day over 4–8 weeks) has resulted in the presence of TUNEL-positive cells in the corpus callosum, altered expression of apoptosis-related genes, and mitochondrial dysfunction [105]. Dose–response relationships are evident, with higher doses correlating with more pronounced apoptotic signatures. Notably, oxidative stress appears to be central to this mechanism; elevated levels of malondialdehyde (MDA) and reduced levels of antioxidant enzymes (SOD, CAT, and GSH) are associated with enhanced apoptotic activation. MPs have also been shown to influence biological pathways leading to endoplasmic reticulum (ER) stress in certain models, which can induce apoptosis via activation of caspase-12 and CHOP [106,107]. Additionally, MPs may trigger ferroptosis or other forms of cell death at higher concentrations, depending on cell type and environmental conditions. Conversely, autophagy activation may initially exert protective effects but becomes detrimental when prolonged, leading to cellular senescence and impaired lysosomal function. Autophagic flux in response to MP exposure has been supported by the autophagy-related genes (ATGs) and markers such as p62 and LC3-II [108,109]. Dysregulation of these pathways may further influence inflammation, immune responses, cancer progression, genotoxicity and DNA damage. Although these findings demonstrated biological plausibility, more experimental exposure levels exceed typical environmental conditions, highlighting the need for chronic low-dose studies to better reflect human exposure scenarios.

3.4. Disruption of Cellular Membrane Integrity

Due to their abrasive surfaces and high surface-area-to-volume ratio, MPs have the potential to damage cell membranes. Interactions between MPs and phospholipid bilayers can lead to calcium ion imbalance, increased membrane permeability, and disruption of membrane integrity [110,111]. Polystyrene (PS) nanoplastics have been shown to penetrate lipid rafts and disrupt these critical structures involved in cell signaling, as demonstrated in studies using Caco-2 cell lines and artificial lipid membranes [112]. The adsorption of proteins onto MP surfaces (formation of a protein corona) further alters their interaction with cells, either promoting endocytosis or inducing phagocytic uptake by immune cells [113]. Depending on its composition and the biological environment, the protein corona may either mitigate or enhance particle reactivity. MP exposure has been linked to metabolic reprogramming, particularly in the liver and adipose tissues. Proteomic and metabolomic studies in exposed organisms indicate differential expression of genes associated with fatty acid β-oxidation, glycolysis, and the tricarboxylic acid cycle. Liver tissues of fish and rodents exposed to MPs demonstrated lipid droplet accumulation and steatosis, suggesting metabolic stress and early-stage non-alcoholic fatty liver disease (NAFLD) [114,115]. These effects are mechanistically linked to disruption of key metabolic regulators such as PPAR, insulin signaling, and AMP-activated protein kinase (AMPK) pathways. Additionally, MPs may indirectly affect energy metabolism through gut microbiota dysbiosis, including altered bile acid metabolism, short-chain fatty acid (SCFA) synthesis, and food absorption [116].

3.5. Endocrine Disruption

Microplastics can act as carriers of endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), phthalates, nonylphenol and heavy metals such as lead, arsenic, cadmium, and mercury. These compounds interfere with hormonal signaling by mimicking or antagonizing endogenous hormones [117]. In reproductive systems, MPs interact with cellular receptors and alter the transcription of steroidogenic enzymes such as CYP19A1, StAR, and 3β-HSD [118]. Several studies have reported that MP exposure leads to altered testosterone and estrogen levels, resulting in disrupted estrous cycles, reduced fertility, and developmental abnormalities. MPs also affect thyroid and insulin regulation. In zebrafish models, polystyrene nano plastics disrupt the hypothalamic–pituitary–gonadal (HPG) axis, reducing sex steroid levels (e.g., 17β-estradiol and testosterone) and impairing gametogenesis [119,120]. These findings are supported by rodent studies demonstrating reduced sperm quality, testicular atrophy, and altered estrous cycles following MP exposure [121,122,123,124].

3.6. Crosstalk Between Mechanisms

There is a significant interaction among these toxicological pathways rather than mutual independence. For example, mitochondrial damage promotes both apoptosis and autophagy, while oxidative stress amplifies inflammatory signaling via the ROS-NF-κB axis. Similarly, DNA damage and endocrine disruption are often interconnected, particularly in relation to reproductive outcomes [125]. Therefore, developing a comprehensive model of MP-induced toxicity requires an integrated understanding of these interconnected mechanisms. The major molecular mechanisms underlying microplastic-induced toxicity, including oxidative stress, inflammation, apoptosis, and endocrine disruption, are summarized in Figure 3.

4. Organ-Specific Toxicity of Microplastics

After ingestion, inhalation, or dermal exposure, microplastics (MPs) can cross epithelial barriers, enter the bloodstream, and accumulate in various organs. Their size, shape, polymer composition, surface properties, and co-contaminant load influence their organotropism and subsequent toxic effects. Numerous in vitro and in vivo studies have demonstrated that MPs exert pro-inflammatory, oxidative, endocrine-disrupting, and cytotoxic effects across multiple biological systems.

4.1. Gastrointestinal Tract

The primary route of microplastic exposure in humans is through the gastrointestinal system, mainly via contaminated food and water. MPs alter mucosal architecture by disrupting tight junction integrity and interacting with gut epithelial cells. Repeated oral exposure to polystyrene (PS) MPs (≤5 µm) has been shown to cause epithelial cell loss and villus atrophy in mice, a condition often referred to as “leaky gut syndrome” [126,127]. This compromised epithelial barrier facilitates systemic translocation of MPs and increases susceptibility to bacterial and endotoxin penetration. Additionally, MPs disrupt the gut microbiota, a key regulator of host metabolism and immunity. Dysbiosis, characterized by altered Firmicutes/Bacteroidetes ratios and reduced microbial diversity, is commonly reported [128]. A summary of experimental studies demonstrating microplastic-induced gastrointestinal toxicity across different model organisms is presented in

Table 1. The table shows the gastrointestinal toxicity induced by microplastics in different model organisms.

S. No.	Model System	MP Type and Size	Exposure Route and Duration	Key Findings	Reference
1.	C57BL/6 mice	PS nano plastics (50–100 nm)	Oral gavage, 4 weeks	Intestinal barrier disruption (occludin/claudin), increased gut permeability; local inflammation (IL-6, TNF-α)	[129]
2.	Zebrafish larvae	PS MPs (1–2 µm)	Waterborne, 7 days	Enterocyte damage, altered gut morphology, increased pro-inflammatory gene expression	[130]
3.	Human Caco-2 intestinal epithelium cells	PS nano plastics (80–100 nm)	In Vitro, 24–48 h	Impaired trans-epithelial electrical resistance (TEER); increased translocation of particles; cytokine release	[131]
4.	Rat colonic epithelial cells (In Vitro)	PS nanoplastics (100 nm)	In Vitro, 24 h	Increased ROS, apoptotic markers (Caspase-3); decreased tight junction protein expression	[132]
5.	Sprague-Dawley rats	PE MPs (20–50 µm)	Oral, 6–12 weeks	Mucosal inflammation, increased MDA, reduced SOD/GSH; altered gut microbiota composition	[77]
7.	BALB/c mice	PS MPs (100 nm)	Oral, 3 weeks	Impaired intestinal development in juveniles; reduced goblet cell numbers; heightened intestinal cytokines	[133]
8.	Human intestinal organoids	PS nano plastics (50–100 nm)	Direct exposure, 48–72 h	Disrupted epithelial differentiation; increased epithelial cell death; barrier dysfunction	[134]
9.	Human fecal microbiome (ex vivo incubations)	Mixed MPs (0.1–10 µm)	Ex Vivo, 24–72 h	Microbiome shifts (Proteobacteria, Firmicutes); altered SCFA production	[135]
10.	ICR mice	PS MPs (1 µm)	Oral, 8 weeks	Villus atrophy, shortened villi, reduced nutrient absorption; gut dysbiosis	[136]

[129,130,131,132,133,134,135,136]. Secondary effects include altered bile acid metabolism, reduced short-chain fatty acid (SCFA) production, and increased intestinal tract inflammation. Furthermore, MPs may interact with co-contaminants such as heavy metals and endocrine-disrupting chemicals (EDCs), exacerbating intestinal barrier dysfunction and microbial pathogenicity.

4.2. Liver

The liver, a central organ for metabolism and detoxification, is a primary site of MP accumulation due to its role in filtering intestinal blood via the portal vein. Histopathological studies have reported hepatic sinusoidal congestion, hepatocellular ballooning, lipid droplet accumulation (steatosis), and inflammatory infiltration following MP exposure [68,137]. Experimental studies in mice, zebrafish, and human hepatocyte models demonstrate hepatocellular degeneration, fibrosis, and inflammation [138]. MPs induce hepatotoxicity primarily through oxidative stress (elevated ROS and MDA levels), reduced antioxidant defenses (SOD, CAT, GSH), and mitochondrial dysfunction. These processes activate pro-inflammatory pathways such as NF-kB and MAPK, resulting in increased cytokines (IL-6, TNF-α) and COX-2. Additionally, MPs disrupt lipid metabolism through deregulation of genes such as PPARα, SREBP-1c, and CYP7A1, leading to lipid accumulation and NAFLD-like phenotypes. Sub-chronic rodent studies have shown that oral exposure to PS MPs or NPs (0.1–10 mg/kg/day for 4–12 weeks) results in hepatic steatosis, increased triglyceride levels, oxidative stress, and inflammation, hallmarks of early-stage NAFLD [77,139]. Molecular evidence further indicates increased lipogenesis (upregulation of SREBP-1c and FAS), and reduced fatty acid β -oxidation (downregulation of PRARα). MPs also interfere with bile acid metabolism and cytochrome P450 enzyme activity, further impairing metabolic homeostasis. A summary of key studies highlighting microplastic-induced hepatotoxicity and associated molecular pathways is presented in Figure 4.

4.3. Kidneys

The renal system, responsible for blood filtration and xenobiotic elimination, is highly susceptible to MP-induced toxicity. Animal studies indicate that prolonged exposure to MPs leads to glomerular hypertrophy, interstitial edema, and impaired renal function, as evidenced by increased serum creatinine and blood urea nitrogen (BUN) levels. MP uptake by renal tubular epithelial cells oxidative stress and reduces nephroprotective proteins such as Nrf2 and HO-1. MPs disrupt glomerular filtration and tubular reabsorption, resulting in proteinuria and electrolyte imbalance. Mechanistically, nephrotoxicity is driven by oxidative stress (increased NOX2 and iNOS) and inflammatory cytokines (IL-1β and MCP-1). A summary of experimental studies highlighting microplastic-induced renal toxicity across different model organisms is presented in

Table 2. The table shows the renal/nephrotoxicity induced by microplastics in different model organisms.

Study No.	Model System	MP Type & Size	Exposure Route & Duration	Key Renal Findings	Reference
1.	C57BL/6 mice	PS nanoplastics (50–100 nm)	Oral gavage, 4 weeks	↑ Serum creatinine/BUN; proximal tubular vacuolization; oxidative stress (SOD, T1MD)	[129]
2.	Sprague-Dawley rats	PS MPs (1 μm)	Oral, 8 weeks	Tubulointerstitial inflammation; apoptosis (Caspase-3); mitochondrial swelling	[133]
3.	Zebrafish (adult)	PS beads (2 μm)	Waterborne, 14 days	Pronephric/mesonephric tubular damage; impaired ion regulation; ROS elevation	[140]
4.	HK-2 human proximal tubule cells	PS nano (80–100 nm)	In Vitro, 24–48 h	Mitochondrial depolarization; DNA damage (γ-H2AX); autophagy flux disturbance	[141]
5.	C57BL/6 mice	PS MPs (500 nm)	Oral, 6 weeks	Fibrosis (TGF-β1/Smad3); collagen deposition; decreased Klotho expression	[81]
6.	Human glomerular endothelial cells	PS nano (100 nm)	In Vitro, 24 h	Endothelial barrier dysfunction; ICAM-1/VCAM-1; increased permeability	[142]
7.	Zebrafish larvae	PS MPs (1 μm)	Waterborne, 7 days	Impaired renal clearance; developmental renal malformations; pro-inflammatory cytokines	[143]
8.	ICR mice	PS beads (5 μm)	Oral, 4 weeks	Transporter dysregulation (OAT1/3, OCT2); impaired xenobiotic excretion	[144]
9.	Wistar rats	Mixed MPs (PS/PE, 0.1–10 μm)	Oral, 12 weeks	Synergistic nephrotoxicity with Cd co-exposure; exacerbated inflammation and fibrosis	[145]

[140,141,142,143,144,145]. Apoptosis is evidenced by Caspase-9 activation and DNA fragmentation. MPs also influence the renin–angiotensin system (RAS), with upregulation of AGT and ACE genes, suggesting a potential link to hypertension and chronic kidney disease (CKD). Furthermore, MPs impair autophagy pathways, leading to lysosomal dysfunction and cellular degeneration.

4.4. Reproductive Organs

Reproductive toxicity induced by MPs is an increasingly significant concern, particularly due to their potential for endocrine disruption and transmission across generations. Exposure to PS-MP has been shown to impair spermatogenesis, reduce testicular weight, and decrease sperm motility and viability in male rats [130]. These effects are primarily mediated through disruption of the hypothalamic–pituitary–gonadal (HPG) axis, downregulation of steroidogenic genes (e.g., StAR, Cyp11a1, and 3β-HSD), and oxidative damage to Sertoli and Leydig cells. In females, reproductive toxicity is characterized by ovarian follicular atresia, disrupted estrous cycles, and reduced oocyte quality. MPs have also been shown to cross the placental barrier, potentially leading to impaired fetal development, low birth weight, and neurodevelopmental abnormalities [146]. Furthermore, MPs can modulate oxidative stress pathways and induce endoplasmic reticulum (ER) stress in granulosa cells, while interfering with estrogen receptor signaling. Transgenerational studies suggest that MP exposure may induce epigenetic modifications, including altered methylation of reproductive gene promoters [147]. MPs also disrupt endocrine homeostasis by interacting with hormone receptors and acting as carriers of endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), phthalates, and polybrominated diphenyl ethers (PBDEs) [148]. These chemicals mimic or antagonize endogenous hormones, affecting both steroidal and peptide hormone pathways. Additionally, MPs may impact the hypothalamic–pituitary–adrenal (HPA) axis, leading to altered stress responses [149]. Changes in circulating corticosterone levels and adrenal histoarchitecture observed in exposed animal models further support the presence of central neuroendocrine disruption [150]. A summary of experimental studies demonstrating microplastic-induced reproductive toxicity across different model organisms is presented in

Table 3. The table shows the reproductive toxicity induced by microplastics in different model organisms.

Study No.	Model System	MP Type & Size	Exposure Route & Duration	Key Reproductive Findings	Reference
1.	C57BL/6 male mice	PS nanoplastics (50–100 nm)	Oral gavage, 4–6 weeks	Reduced sperm count & motility; increased sperm DNA fragmentation; testicular oxidative stress	[151]
2.	Wistar rats (male)	PS MPs (1 μm)	Oral, 8 weeks	Decreased testosterone; Leydig-cell dysfunction; altered steroidogenic genes (StAR, CYP11A1)	[152]
3.	BALB/c female mice	PS MPs (5 μm)	Oral, 6 weeks	Reduced ovarian follicle reserve; increased atresia; elevated ovarian ROS & apoptosis	[153]
4.	Zebrafish (adult)	PS beads (2 μm)	Waterborne, 21 days	Decreased fecundity; impaired oocyte maturation; altered vitellogenin and ESR1 expression	[154]
5.	Sprague-Dawley rats (male)	PE MPs (20–50 μm)	Oral, 10 weeks	Seminiferous tubule degeneration; reduced epididymal sperm quality; increased testicular MDA	[155]
6.	Human granulosa-like cells (KGN)	PS nanoplastics (100 nm)	In Vitro, 24–48 h	Mitochondrial dysfunction; decreased progesterone/estradiol synthesis; apoptosis signaling activation	[144]
7.	Mouse oocytes (IVM)	PS nanoplastics (80 nm)	In Vitro, ≤24 h	Meiotic spindle abnormalities; impaired mitochondrial membrane potential; decreased maturation rate	[156]
8.	Japanese medaka (Oryzias latipes)	PE microfibers (~20 μm)	Waterborne, 28 days	Testis histopathology; reduced GSI; lowered fertilization success	[157]
9.	C57BL/6 mice (gestation)	PS MPs (1 μm)	Maternal oral exposure GD0–GD18	Placental accumulation; fetal growth restriction; altered placental cytokines	[142]
10.	Human trophoblast cells (BeWo)	PS nanoplastics (50–100 nm)	In Vitro, 24–48 h	Barrier dysfunction; increased IL-6/IL-8; reduced hCG secretion	[158]
11.	Male mice (F0–F1)	PS MPs (500 nm–1 μm)	Multigenerational oral, 10 weeks + breeding	Transgenerational sperm defects (F1); altered testis epigenetic marks	[159]
12.	Nile tilapia	PS beads (5 μm)	Waterborne, 30 days	Gonadal inflammation; decreased sex steroid levels; reduced spawning	[160]

[151,152,153,154,155,156,157,158,159,160].

4.5. Central Nervous System

Microplastic-induced Neurotoxicity arises from modulation of oxidative stress and inflammatory pathways, leading to damage in the central nervous system (CNS). Due to their small size, MPs, particularly nanoplastics, can cross the blood–brain barrier (BBB). Polystyrene nanoplastics (50–100 nm) have been detected in brain tissues following oral and intranasal exposure in animal models. These particles induce microglial activation, neuroinflammation, and neuronal damage. Increased levels of pro-inflammatory cytokines (IL-6, IL-1β), oxidative stress markers (NOX4, HO-1) and apoptotic proteins (caspase-3, Bax) have been observed in cortical and hippocampal regions [161]. Behavioral abnormalities, including reduced exploratory activity, anxiety-like behavior, and cognitive impairments (e.g., in object recognition and spatial memory), further confirm the neurotoxic potential of MPs [19,161,162]. A summary of experimental studies demonstrating microplastic-induced central nervous system toxicity across different model organisms is presented in

Table 4. The table shows the central nervous system toxicity induced by microplastics in different model organisms.

Study No.	Model System	MP Type & Size	Exposure Route & Duration	Key CNS Findings	Reference
1.	C57BL/6 mice	PS nanoplastics (50–100 nm)	Oral gavage, 4 weeks	Detected in brain tissue; microglial activation; elevated IL-6, IL-1β; oxidative stress markers (NOX4, HO-1)	[64]
2.	BALB/c mice	PS nanoplastics (50 nm)	Intranasal instillation, 7 days	Crossing of BBB; neuronal apoptosis; impaired spatial memory	[63]
3.	Zebrafish larvae	PS MPs (1 μm)	Waterborne, 7 days	Altered locomotor activity; neurotransmitter imbalance; neuroinflammation	[163]
4.	Human neuroblastoma SH-SY5Y cells	PS nanoplastics (100 nm)	In Vitro exposure, 24 h	Reduced BDNF expression; disrupted calcium signaling; synaptic dysfunction	[164]
5.	Wistar rats	PE MPs (20 μm)	Oral, 6 weeks	Oxidative damage to dopaminergic neurons; behavioral anxiety-like changes	[102]
6.	C57BL/6 mice	PS MPs (500 nm)	Oral, 8 weeks	Epigenetic modifications in brain tissue; altered microRNA expression	[80]
7.	Zebrafish	PS nanoplastics (70 nm)	Waterborne, 10 days	BBB penetration; acetylcholinesterase inhibition; abnormal swimming behavior	[165]
8.	Rat cortical neurons (primary culture)	PS nanoplastics (50 nm)	In Vitro, 48 h	Increased ROS; mitochondrial depolarization; caspase-3 activation	[166]
9.	Sprague-Dawley rats	PS MPs (1 μm)	Oral gavage, 12 weeks	Cognitive deficits in novel object recognition test; hippocampal inflammation	[167]
10.	Human cerebral organoids	PS nanoplastics (100 nm)	Direct exposure, 72 h	Impaired neuronal differentiation; altered synaptic protein expression	[168]

[163,164,165,166,167,168]. In in vitro models, MPs impair synaptic plasticity by reducing brain-derived neurotrophic factor (BDNF) expression and disrupting calcium signaling pathways.

4.6. Cardiopulmonary System

Although ingestion is the primary route of MP exposure, inhalation of airborne microplastics has emerged as a significant concern, particularly in urban and occupational settings. Inhaled MPs deposit in the bronchioles and alveoli, where they interact with pulmonary epithelial cells and macrophages [169]. Experimental inhalation studies in rodents have demonstrated alveolar thickening, goblet cell hyperplasia, fibrosis, and reduced pulmonary compliance. Histological changes include alveolar septal thickening, inflammatory cell infiltration, and epithelial metaplasia. PS and PE fibers have been shown to induce oxidative stress and inflammatory responses in bronchial epithelial cells, increasing IL-8, TGF-β1, and NF-κB signaling [170]. MPs promote epithelial–mesenchymal transition (EMT) and fibroblast proliferation via TGF-β1/Smad signaling, contributing to pulmonary fibrosis. In vitro studies using human bronchial epithelial cells have shown that nanoplastics disrupt tight junction proteins (e.g., occluding, claudin-1), compromising the integrity of the air–blood barrier and facilitating systemic translocation [171,172]. Chronic exposure may increase the risk of asthma, COPD, and pulmonary carcinogenesis due to sustained inflammation and DNA damage [173]. Cardiotoxic effects are primarily secondary to systemic inflammation, oxidative stress, and lipid dysregulation. In zebrafish and rodent models, MPs have been associated with arrhythmias, endothelial dysfunction, and myocardial apoptosis [174]. Endothelial cells exposed to MPs exhibit reduced nitric oxide (NO) bioavailability, impaired vasodilation, and increased expression of adhesion molecules (VCAM-1, ICAM-1), suggesting atherogenic potential [175]. Emerging evidence indicates that MPs are present in human blood and vascular tissues, contributing to oxidative stress and inflammatory signaling pathways involved in cardiovascular diseases. Chronic has been linked to endothelial dysfunction, cardiac hypertrophy, and altered calcium signaling, potentially leading to arrhythmogenic outcomes [176,177,178]. MPs may also act synergistically with other risk factors (e.g., high-fat diet, smoking) to accelerate atherosclerosis [176,179]. A summary of experimental studies demonstrating microplastic-induced cardiopulmonary toxicity across different model organisms is presented in

Table 5. The table shows the cardio-pulmonary toxicity induced by microplastics in different model organisms.

Study No.	Model System	MP Type and Size	Exposure Route and Duration	Key Immunological Findings	References
1.	Humans (carotid plaques, cohort)	PE, PVC MNPs	Observation, 34 mo follow-up	MPs in 60% of plaques; ↑ risk of MI/stroke	[180]
2.	Mice (intratracheal)	PS MPs	Dose–response	Pulmonary fibrosis, oxidative stress	[181]
3.	Human lung epithelial cells	PS NPs	In Vitro	Inflammatory cytokine release	[182]
4.	Zebrafish embryos	PS NPs	Aquatic	Bradycardia, circulation defects	[163]
5.	Human cardiac organoids + mice	PS MPs	Oral + In Vitro	Cardiac hypertrophy, oxidative stress	[183]
6.	Human thrombi (stroke/MI)	Mixed MPs (~35 µm)	Thrombus samples	MPs detected in 80% cases	[184]
7.	Caco-2 endothelial barrier	PS NPs	In Vitro	Translocation across barrier	[185]
8.	Rats (oral gavage)	PS NPs	28 d	Cardiac hypertrophy, apoptosis	[118]
9.	hiPSC-cardiomyocytes	PS NPs (0.05–1 µm)	Long-term exposure	Reduced contractility, Ca2+ dysregulation	[186]
10.	Zebrafish adult	PS MPs	Long-term	Cardiac oxidative stress, arrhythmias	[154]
11.	Rats (90d oral)	PS MPs (0.5 µm)	Drinking water	Apoptosis, fibrosis, Wnt/β-catenin activation	[80]
12.	Mice (coronary artery)	PS NPs	Injection	Endothelial dysfunction	[55]
13.	H9C2 cardio myoblasts	PS MPs	In Vitro	ROS ↑, apoptosis, mitochondrial dysfunction	[127]
14.	HUVECs (endothelial cells)	PS NPs (~50 nm)	In Vitro	Barrier disruption, permeability ↑	[187]
15.	Chicken embryos	PS NPs	Injection	Cardiac malformations	[188]
17.	Mice (42d oral) + H9C2 cells	PS NPs	Oral & culture	Ventricular remodeling, oxidative stress	[189]
18.	Mice (maternal exposure)	PS NPs	Gestational	Offspring cardiac dysfunction	[190]
19.	Human plasma proteomics	MPs detected	Cross-sectional	Correlation with cardiovascular risk	[191]
20.	In Vitro & In Vivo thrombosis	PS NPs	Blood models	Platelet hyperactivation, ↑ thrombus	[156]
21.	Mice (combined PM2.5 + MPs)	PS NPs + PM2.5	Inhalation	Exacerbated lung fibrosis	[15]
22.	Mice (long-term inhalation)	PS NPs	Chronic exposure	Ferroptosis, fibrosis Via cGAS-STING	[107]
23.	Rats (180d oral)	PS MPs	Long-term ingestion	Myocardial fibrosis, inflammation	[192]
24.	Mice (airway instillation)	PS MPs	Intratracheal	Pulmonary inflammation, fibrosis	[168]
25.	Zebrafish larvae	PS MPs	Aquatic exposure	Pericardial edema, reduced HR	[193]

[180,181,182,183,184,185,186,187,188,189,190,191,192,193].

4.7. Immune System

Microplastics act as immunomodulatory agents, distributing both innate and adaptive immune responses. In vitro studies demonstrate that MPs activate macrophages and dendritic cells, leading to increased production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and activation of the NLRP) inflammasome [194,195,196]. However, chronic exposure may lead to immune tolerance, bone marrow suppression, disrupted hematopoiesis, and reduced counts of red and white blood cells [197]. MPs induce oxidative stress and inflammatory signaling (IL-1β, IL-6, IFN-γ) in stromal and progenitor cells, thereby impairing immune function [198,199,200]. Humoral responses are also affected by altered IgA and IgG levels and antigen presentation. MPs have been associated with autoimmune responses, potentially through molecular mimicry or by acting as haptens when bound to adsorbed pollutants. A summary of experimental studies demonstrating microplastic-induced immunological toxicity across different model organisms is presented in

Table 6. The table shows the Immunological toxicity induced by microplastics in different model organisms.

Study No.	Model System	MP Type and Size	Exposure Route and Duration	Key Immunological Findings	Reference
1.	Human THP-1 macrophages (In Vitro)	Polystyrene (100 nm)	Direct exposure, 24 h	Increased IL-1β, TNF-α secretion; activation of NLRP3 inflammasome	[10]
2.	Human PBMCs	PS nanoplastics (50 nm)	Direct exposure, 24 h	Increased ROS; reduced IL-10 production	[201]
3.	Wistar rats	PS MPs (1 µm)	Oral, 8 weeks	Increased serum IgG & IgA; splenic inflammation	[202]
4.	BALB/c mice	PS MPs (500 nm)	Intratracheal instillation, 14 days	Lung macrophage activation; TLR4 upregulation	[203]
5.	Human bronchial epithelial cells	PS fibers (~10 µm)	Airborne exposure, 48 h	IL-8 release; NF-κB activation	[204]
6.	Marine mussels (Mytilus galloprovincialis)	PS beads (2 µm)	Waterborne, 96 h	Hemocyte lysosomal destabilization; reduced phagocytosis	[205]
7.	C57BL/6 mice	PS beads (5 µm)	Oral gavage, 4 weeks	Gut dysbiosis; increased IL-6, IFN-γ; reduced Treg population	[136]
8.	Daphnia magna	PE MPs (10 µm)	Waterborne, 72 h	Altered immune gene expression; reduced survival under infection	[206]
9.	Zebrafish larvae	PS MPs (1 µm)	Waterborne, 7 days	Elevated pro-inflammatory cytokines; neutrophil infiltration	[207]

[201,202,203,204,205,206,207,208]. Peripheral immunotoxic effects include lymphoid organ atrophy (spleen, thymus), reduced antibody production, and increased susceptibility to infections. MPs also alter immune cell polarization (e.g., Th1/Th2, M1/M2 macrophages), maintaining a chronic inflammatory state via TLR4/NLRP3 signaling mechanisms.

4.8. Organ Cross-Talk and Multisystem Impact

Microplastic toxicity is not confined to a single organ system but involves complex organ interactions mediated through endocrine, immune and nervous systems. These interactions contribute to synergistic pathologies. For example, hepatic inflammation may exacerbate cardiovascular dysfunction through systemic cytokine release, while gut barrier disruption (“leaky gut”) may promote neuroinflammation and behavioral alterations via the gut–brain axis. The ability of MPs to act as environmental contaminants (e.g., heavy metals, antibiotics) further amplifies their toxicological impact [207,208]. These interconnected effects highlight the importance of evaluating MP toxicity within an integrated systems biology framework.

4.9. Brief Summary

Organ-specific toxicity of microplastics is driven by common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, and activation of pro-inflammatory pathways such as NF-κB and MAPK. These processes lead to apoptosis, endocrine disruption, and metabolic imbalance in exposed tissues. Structural and functional alterations have been observed in the gastrointestinal tract, liver, kidney, reproductive organs, central nervous system, cardiopulmonary system and immune system. These effects are further amplified by systemic translocation and barrier dysfunction. Chronic exposure may result in cumulative cellular damage and persistent inflammatory signaling. Additionally, inter-organ cross-talks mediated through immune and endocrine pathways further contribute to disease progression. In general, MP toxicity should be considered a multisystem, mechanism-driven health issue rather than isolated specific damage.

5. Conclusions and Future Directions

Microplastics (MPs) are now ubiquitous in the environment, and their potential impacts on human health are increasingly evident. Their small size, environmental persistence, and ability to adsorb and transport toxic contaminants enable them to cross biological barriers and accumulate in various organs. Experimental studies across mammalian and aquatic models demonstrate that MPs and nanoplastics (NPs) induce oxidative stress, inflammation, endocrine disruption, genotoxicity, and immunological dysregulation. Organ-specific toxicities, including hepatotoxicity, nephrotoxicity, neurotoxicity, reproductive toxicity, and cardiovascular dysfunction, have been widely reported. Despite significant mechanistic insights, several knowledge gaps remain. Most toxicological studies rely on short-term, high-dose exposure models, limiting their relevance to real-world human exposure. Long-term effects of chronic low-dose exposure, including bioaccumulation dynamics and transgenerational impacts, remain poorly understood. Standardization of MP characterization and exposure assessment is another major challenge. Variations in particle size, polymer type, surface properties, and reporting metrics hinder cross-study comparisons. Harmonized reporting standards-including particle number, size distribution, surface area, and environmental aging conditions-are urgently needed. Future research should focus on environmentally relevant exposure models, human-relevant systems (e.g., organoids), and advanced toxicokinetic modeling to better understand internal dose–response relationships. Integration of omics approaches and biomonitoring studies will be essential to bridge experimental and epidemiological findings.

Preventive strategies should emphasize the reduction of microplastic sources, improved waste management, the development of safer biodegradable materials, and global regulatory coordination.

In conclusion, although substantial progress has been made in understanding MP toxicity, a unified research framework integrating standardized methodologies of exposure, chronic exposure studies, and human-relevant models is essential to inform risk assessment, regulatory policies, and mitigation strategies for protecting human and environmental health.