To ensure rigor and relevance, we applied explicit inclusion and exclusion criteria for study selection: Inclusion criteria focused on human populations with pathologically confirmed PCa outcomes, reliable PAEs exposure assessment via biomonitoring (urinary metabolites or prostate tissue concentrations), quantitative exposure-outcome associations with statistical significance, rigorous study designs (nested case-control, case-control, cross-sectional, or tissue-urine correlation) with sufficient sample size and adjusted confounders, and publication in peer-reviewed journals with accessible full text. Exclusion criteria included animal/in vitro studies, lack of quantitative associations, unreliable exposure assessment (e.g., only self-reported contact), and duplicate publications. The selected studies were prioritized for their complementary strengths, covering diverse populations, validating key PAEs subtypes/metabolites, and addressing methodological gaps, providing comprehensive support for the PAEs-PCa association.

A population-based nested case-control study (80 PCa cases, 156 controls; 20-year follow-up) in Taiwan identified abdominal obesity (waist circumference ≥90 cm) as a key susceptibility factor, among abdominally obese men, exposure to DEHP, BBzP, and DiBP was significantly positively associated with PCa risk, OR for upper tertile of DEHP metabolites = 7.76, 95% CI: 1.95–30.9, while no such association was observed in non-obese men (Chuang et al., 2020). This nested case-control design minimizes Recall bias (exposure assessed pre-diagnosis). However, it has limited generalizability to non-Asian populations, a gap that is partially addressed by larger cohorts in the U.S. and China. The findings highlight that obesity may potentiate PAEs’ effects, emphasizing targeted protection for high-risk subgroups.

A cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) 2003–2010 data (1,676 men ≥20 years, 100 PCa cases) confirmed a dose-dependent association: the sum of DEHP metabolites (∑DEHP) correlated positively with PCa risk and elevated serum PSA in non-PCa individuals (both p < 0.05), with all PCa-associated PAEs metabolites showing a “higher concentration, higher risk” trend (Guo T. et al., 2023). A large-scale case-control study (187 PCa cases, 151 controls) further validated this, with the highest ∑DEHP exposure group showing a 48-fold higher PCa risk (adjusted OR = 33.02, p < 0.001) (Wang X. et al., 2024). The NHANES cross-sectional design offers population representativeness but cannot establish temporal causality, while the case-control study strengthens outcome specificity (biopsy-confirmed cases, PSA-negative controls) despite residual confounding risks; consistent dose-response trends across designs reinforce the robustness of the DEHP-PCa association.

A case-control study (20 PCa cases, 17 benign prostatic hyperplasia [BPH] cases, 23 healthy controls) identified monoisononyl phthalate (MiNP, a DiNP metabolite) as a specific risk indicator. Urinary MiNP levels were significantly higher in PCa patients than healthy controls (p = 0.014), with concentrations >1 μg/L associated with an OR of 88.02 (95% CI: 3.995–1939, p = 0.005) (Chang et al., 2018). Critical validation came from a tissue-urine correlation study in 76 PCa patients, four PAEs monoesters (monoethyl phthalate [MEP], mono-isobutyl phthalate [MiBP], mono-n-butyl phthalate [MnBP], mono-benzyl phthalate [MBzP]) had a 98.68% detection rate in prostate tissue, with tissue concentrations significantly positively correlated with urinary metabolites (Zhang et al., 2025). While the small-scale case-control study is limited by sample size, its findings are indirectly supported by the biomarker validation study, addressing a key limitation of earlier epidemiological research (uncertainty about target tissue exposure) and confirming urinary metabolites as reliable non-invasive proxies for prostate tissue PAEs exposure.

Collectively, the selected studies confirm three core findings: high-molecular-weight PAEs (DEHP, DBP, BBzP, DiBP) exhibit structure-dependent associations with increased PCa risk; urinary ∑DEHP, MiNP, and MnBP concentrations show dose-dependent correlations with PCa risk, with abdominal obesity potentiating this effect; and urinary MEHP, MnBP, MiBP, and MBzP are validated as non-invasive proxies for prostate tissue exposure. These epidemiological insights provide valuable context for interpreting the molecular mechanisms outlined in Section 3, DEHP’s consistent association with PCa aligns with its documented endocrine-disrupting activity, specifically interference with AR/ER signaling, and its potential to activate oncogenic pathways (MAPK/AP-1, Wnt/β-catenin) in prostate epithelial cells; dose-response trends support the notion that PAEs may act as environmental stressors contributing to carcinogenesis through cumulative cellular perturbations; and the observed PAEs-obesity synergy suggests potential crosstalk between metabolic dysregulation and endocrine disruption, an interplay that may amplify PCa risk. Critically, the validation of urinary biomarkers ensures these epidemiological associations reflect biologically relevant exposure levels in the prostate, addressing a key uncertainty in environmental carcinogenesis research, and thereby supports the plausibility of PAEs’ role in PCa development, while offering an informative framework for connecting population-level observations to the molecular mechanisms detailed in the subsequent section.

The prostate is a sex steroid-sensitive gland dependent on balanced androgen (T) and estrogen (E) signaling for homeostasis (De Falco and Laforgia, 2021). Consequently, any substance capable of disrupting T or E signaling pathways (such as EDCs) may disturb prostate homeostasis, induce pathological changes, and ultimately potentially contribute to PCa progression (Lacouture et al., 2022). Research indicates that an elevated E/T ratio plays a significant role in the development of PCa (Wang et al., 2017). PAEs, as EDCs, disrupt this balance via “anti-androgenic” or “estrogen-mimetic” activities, potentially initiating or exacerbating prostate epithelial cell abnormalities.

PAEs induce heritable epigenetic changes (without altering DNA sequences) that may persistently regulate PCa-related gene expression, providing a foundation for long-term tumor development and progression.

PAEs can target and activate several core signaling pathways in PCa cells. Through a cascade involving upstream kinase phosphorylation, downstream transcription factor activation, and target gene expression, PAEs may directly contribute to tumor cell proliferation, survival, and invasion (Figure 2).

PAEs may drive PCa progression by inducing oxidative stress, disrupting the balance between proliferation and apoptosis, and promoting key phenotypic transitions. Collectively, these alterations enable PCa cells to acquire aggressive traits, enhancing their proliferation, survival, and metastatic capacity.

Early life stages constitute a critical “sensitive window” for organ development, during which exposure to environmental toxins can induce permanent alterations (Basak et al., 2020). Animal studies indicate that perinatal (gestational and lactational) exposure to PAEs disrupts mRNA and protein expression profiles in the ventral prostate of offspring, potentially increasing susceptibility to PCa and other prostatic pathologies, including prostatic intraepithelial neoplasia (PIN), proliferative inflammatory atrophy, and hyperplasia, in aged animals (Aquino et al., 2023; Xia et al., 2018; Peixoto et al., 2016). Supporting this, a study by Xiu Wang et al. demonstrated that DEHP exposure (0.01–1 mg/kg) from gestation day 7 to postnatal day 21 dose-dependently reduced prostate weight in rat offspring. By adulthood (postnatal day 196), these animals exhibited significantly increased PIN incidence, higher Gleason scores, and elevated serum PSA levels, illustrating a clear “developmental-senescence” continuum of potential carcinogenic susceptibility (Wang et al., 2017). Furthermore, multiple studies indicate that prenatal PAEs exposure can lead to shortened anogenital distance (AGD) in male infants and reduced postnatal testosterone levels (Swan et al., 2005; Morová et al., 2020). Epidemiological studies confirm that longer AGD correlates with lower PCa risk (OR = 0.83, 95% CI: 0.70–0.99), suggesting that AGD may serve as a potential epidemiological marker linking fetal PAEs exposure to PCa risk (Castaño-Vinyals et al., 2012).

Beyond transgenerational risk, paternal PAEs exposure disrupts sperm DNA methylation and impairs reproductive function, which may further influence offspring susceptibility. Through mechanisms involving oxidative stress, DNA damage, disruption of the hypothalamic-pituitary-gonadal (HPG) axis, and hormone-like effects, PAEs compromise steroidogenesis and metabolic balance (Høyer et al., 2018). Research by Jurewitz et al. demonstrated that elevated urinary levels of PAE metabolites correlate with reduced sperm motility, lower testosterone, and increased sperm DNA damage and aneuploidy (Jurewicz et al., 2013). DEHP exposure has also been shown to impair human sperm quality and accelerate sperm biological aging directly (Wang Y. X. et al., 2019; Oluwayiose et al., 2022). However, the effects of chronic low-dose exposure remain controversial and warrant further population-based investigation.

Nutritional imbalance and obesity represent significant health challenges in modern society. Existing research indicates that obesity is an established risk factor for aggressive PCa (Gharieb et al., 2024). PAEs’ exposure interacts synergistically with obesity to potentially amplify carcinogenic risk. Epidemiological studies reveal a positive correlation between prenatal PAEs exposure and childhood obesity/overweight status (Shree et al., 2022). Research by Akritidis et al. indicates that DEHP and its metabolites correlate positively with overall obesity (Akritidis et al., 2025). Notably, PAEs’ lipophilic nature facilitates accumulation in adipose tissue, where they can activate peroxisome proliferator-activated receptor gamma (PPARγ), thereby disrupting cholesterol metabolism and sex hormone synthesis (Chuang et al., 2020; Del Río Barrera et al., 2025; Elix et al., 2018).

This interaction creates a vicious cycle. In obesity, increased adipose tissue aromatase activity elevates estradiol levels. This effect synergises with the inherent estrogenic properties of PAEs, further disrupting the E/T balance and potentially driving PCa proliferation and castration-resistant progression (Chuang et al., 2020). Furthermore, PAEs stored in adipose tissue can be released into the bloodstream during weight loss, exacerbating endocrine disruption (Dirtu et al., 2013). Thus, the “PAE exposure → obesity → enhanced PAE bioaccumulation → amplified PCa risk” cycle highlights a critical pathway through which metabolic status and environmental chemical exposure jointly may influence cancer susceptibility.

Preventing the environmental release of PAEs forms the foundational layer of the prevention system, directly determining overall population exposure levels. Legislative action is essential to restrict the use of HMW-PAEs (e.g., DEHP, DBP), which are closely associated with PCa risk, in high-exposure products such as food packaging and medical devices (Zhou et al., 2025). Concurrently, industrial emissions of PAEs in waste gasses, wastewater, and residues must be strictly regulated to reduce pollution at its source. Environmental and biological monitoring can leverage advanced technologies, such as ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), to establish a PAEs exposure surveillance network. This enables precise quantification of PAE metabolite levels in urine and tissues, providing crucial data for tracing regional pollution and assessing population risk (Zhang et al., 2025). The integration of computational approaches, such as molecular docking simulations, further supports the development of early warning systems in high-risk areas (Zhang T. et al., 2021; Liu et al., 2025). In the long term, developing and validating safe alternative materials is paramount. Efforts should be accelerated to promote substitutes like triethyl acetyldimonium citrate (ATEC), which exhibit no estrogenic or anti-androgenic activity (Xu et al., 2019; Park et al., 2019). Evidence confirms that policy interventions restricting PAEs in consumer products can significantly reduce urinary metabolite concentrations in the population, thereby indirectly lowering potential PCa risk associated with PAEs exposure (Sieck et al., 2024).

Building on source control, implementing targeted protection for populations with heightened vulnerability is essential to maximize risk reduction. Maternal-fetal populations, as core targets for PAEs’ transgenerational effects, require special attention since perinatal exposure alters offspring prostate mRNA and protein expression profiles, potentially increasing adult PCa susceptibility (Aquino et al., 2023). While human epidemiological data link prenatal PAEs exposure to shortened AGD (Lu et al., 2024). Pregnant women should be advised to minimize contact with disposable plastic products, and PAEs exposure risks should be incorporated into standard prenatal health education. Patients undergoing PCa treatment must be aware that PAEs can interfere with therapeutic efficacy; for instance, DBP may promote tumor progression by competitively binding to the AR or activating ERα, potentially undermining androgen deprivation therapy (ADT) (Zhang T. et al., 2021). Therefore, integrating exposomics monitoring into clinical management is advisable. For instance, urine samples could be collected during procedures like robot-assisted prostatectomy to monitor PAEs metabolite levels dynamically, informing personalized therapy adjustments (Tsai et al., 2025).

Furthermore, occupational groups such as plasticizer manufacturers, plastic processors, healthcare workers, and firefighters face elevated PCa risk due to prolonged exposure at high concentrations (Eckert et al., 2023; Park et al., 2024; Kolena et al., 2020; Janjani et al., 2024; Shi et al., 2024; Shi et al., 2023; Nguyen et al., 2022). Tailored protective standards for these groups are necessary, including defined exposure limits, provision of chemical-resistant personal protective equipment, and the establishment of routine biomonitoring programs. Linking occupational exposure data to PCa incidence in a dedicated database would support evidence-based updates to safety guidelines.

Expanding interventions to the general population can further reduce daily exposure risks through integrated public education, policy, and lifestyle modifications. Public health education should target high-exposure scenarios and priority groups. For children and adolescents who frequently use plastic products, studies show significant correlations between urinary PAE metabolite levels and health risks, necessitating advocacy for reducing reliance on single-use plastics (Wang Y. et al., 2024). Specific consumer products require management, as the use of some sunscreens has been linked to elevated urinary levels of mono-n-hexyl phthalate (MnHxP), likely due to the presence of di-n-hexylphthalate (DnHxP)/MnHxP (Frederiksen et al., 2025). Regulatory bodies can establish safety thresholds, as exemplified by the EU Scientific Committee on Consumer Safety (SCCS), which recommends a maximum limit of 260 ppm for DnHxP as a byproduct, or below 1 ppm if present as an unavoidable impurity (Scherer et al., 2025). Dietary intervention is another critical measure, as approximately 90% of human PAEs exposure stems from contaminated water or food (Wang et al., 2023). Studies indicate that high PAEs exposure indices are typically associated with consuming takeout food, using plastic containers and packaging, and employing children’s cosmetics and bath products (Jung et al., 2025). Therefore, dietary habits should be adjusted to reduce intake of processed foods, thereby decreasing exposure to HMW-PAEs, or substitute PCPs to minimize exposure to LMW-PAEs (Ma et al., 2019; Wu et al., 2025; Yang et al., 2023). Additionally, glass or ceramic containers should be prioritized over plastic containers for food preparation and storage (Hall and Greco, 2019). Research also suggests folate supplementation may reduce urinary PAEs metabolite concentrations (Huang et al., 2025). Women planning or during pregnancy are advised to consume folate through diet or supplements to mitigate PAEs accumulation (Chen et al., 2025).

Fostering multidisciplinary collaboration between environmental medicine and oncology is essential to integrate PAEs exposure assessment into the routine care pathway for PCa, thereby achieving a closed-loop management system from prevention to treatment. For instance, incorporating urinary PAEs metabolite testing (e.g., MEHP, MnBP) into preoperative evaluations and postoperative follow-ups for PCa patients, combined with PSA levels and Gleason scores, can dynamically adjust treatment plans. Particularly for patients undergoing ADT, drug dosages should be optimized based on exposure levels. Given the DOHaD-derived risk of transgenerational susceptibility, clinical counseling for PCa patients with a history of early-life PAEs exposure (e.g., maternal use of plastic products during pregnancy) should include recommendations for offspring to minimize PAEs exposure and to undergo regular PCa screening. Future efforts should prioritize longitudinal studies to validate the efficacy of these integrated interventions. The ultimate goal is to progressively establish an individualized risk-warning system, informed by pharmacogenomics and continuous biomonitoring. This approach aims to achieve comprehensive risk management spanning from pollution control at the source to endpoint patient protection, ultimately improving outcomes for PAEs-exposed PCa patients.

While epidemiological studies have highlighted associations between specific high-molecular-weight PAEs (e.g., DEHP, DBP) and PCa risk, real-world exposure involves complex mixtures of multiple PAEs and other EDCs (Liang et al., 2025). Future work should focus on identifying which PAE subtypes play pivotal roles in prostate carcinogenesis through large-scale prospective cohorts and multi-center validations. This includes quantifying the independent and combined contributions of specific PAEs metabolites to PCa initiation and progression, and elucidating potential synergistic, additive, or antagonistic interactions in “cocktail” exposure scenarios. For instance, studies have shown that mixtures of PAE metabolites can induce oxidative stress and enhance migratory capacity in prostate cancer cells (Cavalca et al., 2022), while co-exposure to PAEs and trace elements may exacerbate oxidative damage in PCa patients (Chang et al., 2018). Additionally, interactions between PAEs and bisphenols (another class of EDCs) have been implicated in PCa occurrence, highlighting the need for comprehensive mixture risk assessment (Wang X. et al., 2024).

Developing integrated exposure assessment tools that combine environmental monitoring, biomonitoring (e.g., urine, blood, tissue PAEs metabolites), and dietary surveys will be essential for accurately characterizing individual cumulative exposure. For example, simultaneous detection of PAEs monoesters in prostate tissue and urine has provided reliable biomarkers for exposure assessment (Zhang et al., 2025), which can be expanded to mixed exposure scenarios to refine risk prediction models.

Although animal studies indicate transgenerational carcinogenic risks following perinatal PAEs exposure, the specific epigenetic mechanisms underlying this heritable susceptibility in humans remain poorly defined (Wang et al., 2017). Future research should decipher the patterns of transgenerational epigenetic inheritance, focusing on alterations in DNA methylation, histone modifications, and non-coding RNA profiles (e.g., miRNAs, lncRNAs, circRNAs), induced by maternal and paternal PAEs exposure (Ho et al., 2017).

Preclinical studies have provided critical clues: maternal exposure to PAE mixtures can alter miRNA expression and transcriptome profiles in offspring prostate tissue, linking developmental exposure to PCa risk (Aquino et al., 2023; Aquino et al., 2024). Specifically, in utero and lactational DEHP exposure increases prostate carcinogenesis susceptibility in offspring by inducing PSCA hypomethylation (Xia et al., 2018), whereas MEHP can induce DNA hypomethylation in LNCaP cells, disrupting genomic stability (Wu et al., 2017). Longitudinal cohort studies tracking these epigenetic changes across generations, coupled with functional validation in experimental models, are needed to identify stable epigenetic markers associated with increased PCa risk. The ultimate goal is to integrate these epigenetic signatures with conventional risk factors (e.g., age, family history, obesity) to construct early-warning models that identify individuals at high lifetime risk of PCa.

The synergistic interplay between PAEs exposure and obesity appears to amplify PCa risk, but whether this interaction is reversible remains an open question. Existing evidence confirms that combined exposure to PAEs and a high-fat diet can induce histopathological alterations in the prostate (de Jesus et al., 2015), while PAE exposure correlates with abdominal obesity and may disrupt lipid metabolism, thereby exacerbating carcinogenicity (Akritidis et al., 2025).

Future studies should explicitly test the reversibility of metabolic-chemical interactions through well-designed intervention trials in obese populations with documented high PAEs exposure. Key inquiries include whether weight loss, dietary modifications, or increased physical activity can reduce PAE body burden, restore endocrine homeostasis, and mitigate associated cancer risks. Concurrently, the potential of nutritional supplements to reverse PAEs-induced epigenetic dysregulation should be evaluated: population-based studies have shown that serum and red blood cell folate concentrations are associated with reduced urinary PAEs metabolite levels (Huang et al., 2025), while folic acid and vitamin D may modulate the adverse effects of prenatal PAEs exposure (Chen et al., 2025). These efforts will inform the development of personalized intervention protocols for PCa patients and high-risk individuals, combining exposure reduction, metabolic management, and adjuvant therapies to improve outcomes.

To bridge the gap between mechanistic understanding and real-world impact, future research must foster closer integration of basic science with clinical and public health practice.

At the therapeutic level, translating key mechanistic findings into targeted strategies is critical. For example, MEHP-induced PCa progression involves activation of the Hh pathway and Wnt/β-catenin signaling, providing potential targets for small-molecule inhibitors (Li et al., 2023; Yong et al., 2016). Network toxicology and molecular docking approaches have identified key interaction targets of PAEs metabolites in PCa cells, laying the groundwork for drug development (Liang et al., 2025). Additionally, incorporating urinary PAEs metabolites and relevant epigenetic biomarkers into PCa screening, diagnosis, and prognostic assessment could enhance early detection and risk stratification. For instance, urinary MiNP levels >1 μg/L are associated with a significantly increased PCa risk (Chang et al., 2018), while specific miRNA signatures (e.g., miR-34a, miR-205) altered by PAEs exposure may serve as complementary biomarkers (Tsai et al., 2025; Zhu et al., 2019).

At the policy level, evidence from population-based intervention studies should directly inform regulations: policy restrictions on PAEs use in consumer products have been shown to reduce urinary metabolite concentrations (Sieck et al., 2024), supporting the promotion of safer alternatives (e.g., citrate ester plasticizers) to achieve primary prevention at the population level (Xu et al., 2019).