How Microplastics and Hormone-Disrupting Chemicals May Cause Cell Damage and Affect Health

Growing evidence suggests that MPs/NPs adversely affect cardiovascular structure and function. Following inhalation or ingestion, small plastic particles can translocate into systemic circulation and interact directly with vascular endothelial cells [3]. In vitro and in vivo studies demonstrate that MP exposure induces endothelial dysfunction characterized by increased reactive oxygen species (ROS) production, reduced nitric oxide bioavailability, and impaired vasodilation [4]. Oxidative stress-driven activation of NF-κB and MAPK signaling promotes vascular inflammation, increasing expression of pro-inflammatory cytokines such as TNF-α and IL-6, which are key contributors to atherogenesis [5].

Recent animal studies further indicate that chronic MP exposure accelerates lipid accumulation, macrophage infiltration, and plaque instability in vascular tissues, suggesting a potential role in atherosclerosis progression [6]. Notably, MPs have been detected in human blood and atherosclerotic plaques, providing direct evidence of cardiovascular exposure and raising concerns about long-term cardiometabolic risk [2,7]. In addition, MP-induced endocrine disruption, particularly altered lipid and glucose metabolism, may indirectly exacerbate cardiovascular disease risk through metabolic dysregulation.

The nervous system is particularly vulnerable to MP/NP exposure due to the ability of nanoplastics to cross the blood–brain barrier and accumulate in brain tissue [44]. Animal studies have detected MPs/NPs in the cortex, hippocampus, and olfactory bulb, regions critical for cognition, memory, and sensory processing [45]. Neurotoxicity is largely mediated by oxidative stress, mitochondrial dysfunction, and neuroinflammation, with microglial activation and elevated levels of IL-1β and TNF-α commonly reported following exposure [13].

MP-induced disruption of calcium signaling and mitochondrial membrane potential further amplifies ROS production, leading to synaptic damage and neuronal apoptosis [46]. Neurotransmitter systems are also affected, with reported alterations in dopamine, acetylcholine, and glutamate pathways, resulting in behavioral changes such as anxiety-like behavior, impaired learning, and memory deficits in animal models [47]. Of particular concern is early-life exposure, as prenatal and neonatal MP exposure has been linked to abnormal neurodevelopment, altered synaptic plasticity, and long-lasting cognitive impairment [47]. These findings raise important questions regarding the potential contribution of MPs/NPs to neurodevelopmental and neurodegenerative disorders in humans.

The reproductive system represents one of the most consistently affected targets of MP/NP exposure. MPs act as both sources and carriers of EDCs, including bisphenols and phthalates, which interfere with hormone receptor signaling and steroidogenesis [16,18]. In male reproductive systems, MP exposure has been associated with reduced sperm count, impaired sperm motility, testicular oxidative stress, and disruption of testosterone synthesis through altered expression of steroidogenic enzymes such as CYP11A1 and CYP17A1 [13].

In females, MPs/NPs accumulate in ovarian and uterine tissues, leading to follicular atresia, altered estrous cycles, and disrupted estrogen and progesterone balance [16,18,48]. Placental accumulation of MPs has been reported in both animal models and humans, raising concerns about impaired placental function, fetal hormone exposure, and developmental programming effects [1]. Importantly, several studies demonstrate dose- and time-dependent accumulation of MPs/NPs in reproductive organs, suggesting that chronic low-level exposure may result in progressive reproductive toxicity even in the absence of acute effects [48,49].

When cells are exposed to microplastics, they rapidly begin generating excessive amounts of ROS. Although some ROS arise from chemical interactions at the particle surface, the majority are produced intracellularly. Once micro- or nanoplastics enter the cell, they can accumulate in mitochondria and other organelles, where they interfere with normal electron transport and disrupt redox homeostasis. Studies show, for example, that polystyrene microplastics induce dose- and concentration-dependent increases in ROS across multiple cell types and animal models [1,2,3,4]. Mechanistically, nanoplastics and microplastics impair the mitochondrial electron transport chain, promoting electron leakage and the formation of superoxide and other reactive species [3,4,5]. In parallel, both the particles and associated chemicals—such as bisphenol A (BPA)—can activate ROS-producing enzymes like NADPH oxidase, further amplifying oxidative stress [6,7].

Under mild oxidative stress, cells attempt to restore balance by upregulating antioxidant defenses, largely through the Nrf2–Keap1 signaling pathway. Under basal conditions, Keap1 retains Nrf2 in the cytoplasm and targets it for degradation. When ROS oxidize critical cysteine residues in Keap1, Nrf2 is released, translocates to the nucleus, and induces the transcription of antioxidant and cytoprotective genes [8,9]. These include genes encoding key enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) [8,10]. Low-level microplastic exposure can trigger this transient protective response, reflected by an initial increase in antioxidant enzyme activities and glutathione-related defenses [4,10,11]. When ROS generation becomes excessive or sustained, however, this defense system is progressively compromised. Antioxidant enzymes may be inactivated or depleted, and intracellular glutathione pools become oxidized, leaving cells unable to neutralize accumulating ROS [11,12]. As oxidative stress intensifies, ROS begin to damage essential cellular components, including lipids, proteins, and DNA. Lipid peroxidation—one major consequence—produces reactive aldehydes such as malondialdehyde, which is consistently elevated in tissues and organs exposed to microplastics [11,12]. Experimental evidence consistently demonstrates that micro- and nanoplastic (MP/NP) exposure induces lipid peroxidation in a dose-dependent manner, with increasing concentrations and longer exposure durations leading to progressive elevations in malondialdehyde (MDA) and other lipid oxidation products, alongside depletion of antioxidant defenses such as superoxide dismutase and glutathione peroxidase [6,14,48]. Notably, nanoplastics often elicit stronger lipid peroxidation responses than larger microplastics at comparable mass doses, reflecting enhanced cellular uptake, greater surface reactivity, and increased mitochondrial dysfunction [46]. In vivo biodistribution studies further reveal dose- and time-dependent accumulation of MPs/NPs in multiple organs following oral or inhalation exposure, with the highest burdens typically observed in the gastrointestinal tract and liver, followed by the kidney, lung, spleen, heart, brain, and reproductive organs [47,48,49]. Importantly, nanoplastics demonstrate a greater ability to cross biological barriers, including the blood–brain and placental barriers, raising concerns about neurodevelopmental and reproductive toxicity under chronic low-dose exposure conditions [46,47]. Together, these findings indicate that MP/NP toxicity is strongly influenced by exposure dose, particle size, and cumulative tissue accumulation, with lipid peroxidation serving as a mechanistic link between particle burden and organ-specific oxidative injury. Similarly, microplastic-induced ROS can cause DNA strand breaks and oxidative base modifications, reflected in increased levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and positive comet assay results [28,29]. In summary, microplastic exposure leads to chronic oxidative stress driven by excessive ROS production and weakened antioxidant defenses—a combination that sets the stage for widespread cellular dysfunction [4,5].

Mitochondria are especially vulnerable to the oxidative damage induced by MPs and NPs. As the cell’s primary energy producers and a major endogenous source of ROS, mitochondria can undergo severe functional decline when microplastics accumulate intracellularly. Electron microscopy studies have confirmed that both nano- and microplastics enter cells and localize to mitochondrial compartments, provoking mitochondrial membrane depolarization, structural disruption, and markedly reduced ATP output. For instance, one study found that human fibroblasts exposed to nanoscale polystyrene particles exhibited mitochondrial swelling, loss of membrane potential, diminished ATP production, and cytochrome c leakage—hallmark features of oxidative stress-driven apoptosis [49,50].

This mitochondrial compromise is tightly linked to ROS overproduction: disruptions of the tricarboxylic acid cycle and oxidative phosphorylation by microplastics lead to enhanced electron leakage, which generates excess ROS and further impairs mitochondrial enzyme function [51,52]. As oxidative injury accumulates, cells frequently initiate regulated cell-death pathways. Prolonged exposure to microplastics has been associated not only with mitochondrial-mediated apoptosis (via cytochrome c release and caspase activation) but also with non-apoptotic death modalities such as necroptosis and ferroptosis under conditions of pronounced ROS elevation [53,54,55].

Beyond mitochondria, microplastic-induced oxidative stress can also provoke endoplasmic-reticulum stress and activate the unfolded protein response. In ovarian cells of animals exposed to microplastics, activation of the PKR-like ER Kinase (PERK)–eukaryotic Initiation Factor 2 alpha (eIF2α)—Activating Transcription Factor 4 (ATF4)–C/EBP-Homologous Protein (CHOP) axis has been observed, suggesting that unresolved ER stress—likely driven by ROS and calcium dysregulation—contributes to organ-specific cellular damage [56,57,58,59]. Collectively, mitochondrial dysfunction and ER stress form an interlinked cascade of deleterious events rooted in the oxidative burden imposed by microplastics (Figure 1). Calcium signaling plays a critical role in micro- and nanoplastic–induced cellular stress and is closely linked to reactive oxygen species (ROS) generation. Exposure to micro/nanoplastics disrupts intracellular Ca²⁺ homeostasis by promoting Ca²⁺ influx through plasma membrane channels and release from intracellular stores such as the endoplasmic reticulum, leading to cytosolic Ca²⁺ overload [60,61,62]. Elevated Ca²⁺ levels stimulate mitochondrial Ca²⁺ uptake, which impairs mitochondrial membrane potential and enhances mitochondrial ROS production, thereby amplifying oxidative stress [13,63]. In parallel, Ca²⁺-dependent activation of NADPH oxidases further contributes to ROS amplification, creating a feed-forward loop between Ca²⁺ dysregulation and oxidative damage [15]. Collectively, these findings suggest that Ca²⁺ signaling acts as an important upstream modulator of ROS generation and oxidative injury following micro- and nanoplastic exposure.

The chemical additives associated with microplastics—particularly BPA and phthalates—have independent toxic effects that intensify both oxidative stress and endocrine disruption, thereby amplifying the overall biological impact of microplastics. BPA, a well-characterized synthetic estrogen, can bind to estrogen receptors and other signaling proteins, leading to broad disturbances in cellular homeostasis [18,63,64]. BPA exposure is widely reported to increase intracellular production of ROS and to activate oxidative stress–mediated apoptotic pathways [65,66,67]. In ovarian granulosa cells, for example, BPA activates the G-protein–coupled estrogen receptor (GPER), triggering a calcium influx and subsequent activation of the ASK1–JNK signaling cascade, ultimately resulting in ROS-driven apoptosis [68].

BPA’s pro-oxidant effects are closely linked to mitochondrial dysfunction. It can uncouple oxidative phosphorylation, impair ATP generation, and suppress key antioxidant enzymes, contributing to redox imbalance [66,69]. These mitochondrial and oxidative disruptions have been associated with impaired oocyte maturation and reduced sperm quality in multiple animal models [69,70].

Phthalates—particularly di-(2-ethylhexyl) phthalate and its metabolite mono-(2-ethylhexyl) phthalate —exert similar oxidative effects. Due to their lipophilic nature, phthalates integrate into cellular membranes, promoting lipid peroxidation, elevating ROS production, and depleting intracellular glutathione stores [6,71]. A broad review of animal studies shows that chronic phthalate exposure consistently produces oxidative stress, marked by increased levels of malondialdehyde and 8-OHdG, along with significant reductions in antioxidant enzymes such as superoxide dismutase and glutathione peroxidase [6,71,72]. These oxidative alterations are strongly implicated in reproductive dysfunction, hepatic injury, and metabolic disturbances [61,72].

Additionally, both BPA and phthalates can interfere with mitochondrial electron transport and activate redox-sensitive transcription factors, further contributing to cellular oxidative burden [6,66]. Together, these findings indicate that microplastics and the endocrine-disrupting chemicals they leach act through overlapping mechanisms—direct ROS generation, suppression of antioxidant defenses, mitochondrial impairment, and membrane damage—making oxidative stress a central driver of their toxicity.

Exposure to microplastics—and particularly to the EDC additives they transport—can profoundly interfere with endocrine regulation. Many plastic additives are well-characterized EDCs capable of mimicking, antagonizing, or dysregulating endogenous hormone functions. BPA, for example, binds to estrogen receptors ERα and ERβ, as well as other hormone-responsive receptors, thereby disrupting downstream signaling and altering gene transcription profiles linked to reproductive and metabolic processes [18,65]. Likewise, phthalates such as di(2-ethylhexyl) phthalate and its bioactive metabolite MEHP interact with nuclear receptors including the peroxisome proliferator-activated receptors (PPARs), leading to dysregulation of lipid metabolism, steroidogenesis, and overall endocrine homeostasis [66].

These receptor-level interactions translate into measurable physiological disturbances. Multiple studies indicate that microplastic exposure disrupts several hormonal axes, prominently the hypothalamic–pituitary–gonadal (HPG) axis. In aquatic models, chronic exposure to polystyrene nanoplastics suppresses HPG-axis activity: reduced expression of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) genes in the brain, decreased circulating sex-steroid concentrations (estradiol and testosterone), and marked reproductive impairment including fewer eggs laid and reduced hatching rates [67]. Similar findings have been documented in mammalian systems. Rodents exposed orally to polystyrene microplastics show significant reductions in key reproductive hormones (follicle- stimulating hormone, LH, and estradiol), along with histopathological damage to ovarian follicles and testicular seminiferous tubules. These effects are dose- and time-dependent, suggesting cumulative endocrine toxicity with sustained microplastic exposure [64].

Microplastic-associated endocrine disruption is not restricted to reproduction. Other endocrine organs are equally susceptible. BPA has been shown to alter thyroid hormone receptor signaling and interfere with enzymes essential for thyroid hormone synthesis and metabolism, resulting in abnormal thyroxine and triiodothyronine levels [8,65]. Human epidemiological studies report correlations between elevated urinary BPA or phthalate metabolites and altered thyroid parameters—including abnormal TSH and thyroxine concentrations—raising concerns about population-level thyroid disruption [72]. Emerging animal evidence also suggests that nanoplastic exposure may influence adrenal function, reflected in altered cortisol levels in fish and corticosterone fluctuations in rodents, although this area warrants further research [53,67].

A recent comprehensive review concluded that MPs and NPs can disrupt endocrine functions across the entire neuroendocrine axis—from central regulators (hypothalamus, pituitary) to peripheral glands (thyroid, adrenal, gonads)—and that many of these effects are mediated, at least in part, through oxidative-stress pathways [3]. Oxidative damage in steroidogenic tissues such as the ovary and testis can impair hormone biosynthesis, while oxidative injury to thyroid follicular cells may reduce hormone production and promote local inflammation. Moreover, endocrine imbalance can itself exacerbate oxidative stress—for instance, estrogen deficiency weakens antioxidant defenses, potentially creating a self-perpetuating cycle of hormonal and oxidative dysfunction [3].

Microplastics induce endocrine disruption and hormonal imbalance through a close and bidirectional interaction with oxidative stress. Exposure to micro- and nanoplastics increases reactive oxygen species production, which directly impairs steroidogenic enzyme activity (e.g., CYP11A1, CYP17A1, aromatase) and alters hormone synthesis in gonadal and adrenal tissues [14,16]. Oxidative stress also modifies hormone receptor structure and signaling sensitivity via lipid peroxidation and redox-dependent post-translational modifications, thereby disrupting estrogen, androgen, thyroid, and glucocorticoid receptor pathways [15,18]. In parallel, endocrine-disrupting chemicals associated with microplastics further exacerbate oxidative stress by impairing mitochondrial function and antioxidant defenses, creating a feed-forward loop between redox imbalance and hormonal dysregulation [14,17]. Together, these interactions provide a mechanistic framework linking microplastic-induced oxidative stress to sustained endocrine disruption and systemic hormonal imbalance.

These disruptions carry significant clinical implications. Endocrine-active microplastics and their associated EDCs may contribute to otherwise unexplained cases of infertility, developmental abnormalities, metabolic dysregulation, and thyroid disease. For reproductive specialists and endocrinologists, this highlights the importance of incorporating environmental exposure screening into routine diagnostic evaluation, especially as microplastic contamination represents an emerging and increasingly unavoidable component of modern environmental health (Figure 2).

MPs/NPs together with their associated EDCs, have been shown to induce profound alterations in the metabolome, reflecting systemic metabolic dysregulation. Experimental metabolomics studies consistently report dose- and size-dependent disturbances in lipid, amino acid, carbohydrate, and energy metabolism following MP/NP exposure, with nanoplastics generally exerting stronger effects due to enhanced bioavailability and cellular uptake [14,47,48]. Disruption of lipid metabolism is a prominent feature, characterized by altered phospholipids, fatty acids, and sterol intermediates, which is closely linked to oxidative stress–induced lipid peroxidation and impaired mitochondrial β-oxidation [6,47]. In parallel, MP-associated EDCs such as bisphenols and phthalates interfere with nuclear receptor signaling (e.g., PPARs, estrogen and androgen receptors), leading to reprogramming of metabolic pathways involved in glucose homeostasis, insulin sensitivity, and lipid storage [16,18]. Metabolomic analyses further reveal disruptions in amino acid pathways, including branched-chain amino acids and glutamine–glutamate metabolism, suggesting impaired protein turnover and redox balance [14]. Importantly, in vivo studies demonstrate that these metabolomic shifts often coincide with tissue accumulation of MPs/NPs in metabolically active organs such as the liver, intestine, and adipose tissue, supporting a mechanistic link between particle burden, endocrine disruption, and metabolic reprogramming [49,50]. Collectively, these findings indicate that MP/NP exposure, amplified by co-exposure to EDCs, reshapes the metabolome through integrated effects on oxidative stress, hormone signaling, and mitochondrial function, potentially contributing to metabolic disorders and long-term cardiometabolic risk.

No new data were created or analyzed in this study. Data sharing is not applicable to this article.