{"paper_id":"aefb6bf8-7325-4de3-9f06-43f5d754998c","body_text":"Hormone-dependent cancers are increasingly becoming more prevalent worldwide, with higher diagnosis rates in high-income countries and higher mortality in low- to middle-income countries 1 . Estrogens are particularly involved in the development of endometrial, ovarian, and breast cancers 2 , and are implicated in the progression of cervical cancer in women 3  and prostate cancer in men 4 . The surge in the incidence of estrogen-mediated cancers parallels increased exposure to synthetic or natural compounds that mimic the activity of estrogens, known as endocrine disrupting compounds (EDCs). EDCs have been associated with high body mass index 5 , which has also been associated with increased risk of endometrial 6  and breast 7  cancers. Among the EDCs, paraben esters constitute a large group of chemicals commonly found in food, personal care and hygiene products, and other everyday items.\nParabens have been associated with several cancers, more specifically with an increased risk of breast cancer 8 , 9 , and have been observed to accumulate at higher levels in cancer tissue compared to healthy tissue 8 . Moreover, in vitro and ex vivo models have provided mechanistic insights into cancer-associated adverse outcomes of parabens 10 , 11 . These compounds exert estrogenic effects by activating estrogen receptors, enhancing the production or actions of natural estrogens, and increasing circulating estrogen levels by inhibiting sulfotransferase enzymes that are responsible for the excretion of estrogens from the body 12 . Despite the evidence of estrogenic activity and detection of parabens in certain cancer tissues, the relationship between parabens and estrogen-mediated cancers remains poorly understood due to the complex contribution of various intrinsic and environmental cofactors, inter-individual differences, and the rather chronic nature of health effects of these molecules. It is unclear whether these associations are merely coincidental, indicative of a causative role, and/or whether the cancer is a consequence of paraben exposure. Moreover, health disparities in exposure patterns and mechanistic links are not well understood.\nIn this review, we provide our insights on parabens and estrogen-mediated cancers by presenting an overview of clinical studies concerning cancer patients and individuals with non-cancerous conditions (i.e., infertility, endometriosis, etc.), utilizing targeted or untargeted metabolomics approaches. Additionally, we present novel data on parabens detected in the local cervicovaginal microenvironment of patients newly diagnosed with cervical or endometrial cancer. We discuss the factors impacting the exposure patterns and summarize findings from cell/tissue culture and animal models to highlight potential mechanisms of action. Our focus within the scope of this review is primarily on cancers affecting women’s health.\n\nSince their introduction in the 1950s as preservative agents, paraben molecules have been increasingly incorporated in the formulation of everyday products to extend the shelf life of cosmetics, pharmaceuticals, food and drinks, and various personal care products (PCP) including sunscreen, makeup, toothpaste, shampoo, and feminine hygiene products 13 . Epidemiological studies investigating the association between PCP use and cancer risk have yielded inconsistent results. For example, PCP use during puberty ( n  = 45,465) has been associated with an increased risk of breast cancer 14 , whereas a prospective cohort study ( n  = 106,978) did not find any association between PCP and breast or endometrial cancer risk 15 . However, these studies largely rely on self-reported product use and do not account for the specific chemical constituents of PCPs, limiting their ability to identify associations with individual compounds. Regardless, the widespread use of these products combined with the physicochemical characteristics of the parabens has led to their accumulation in soil, water, and air 16 , consequently contaminating food and drinks and potentially causing indirect exposure. Collectively, this may exacerbate the health threat and require “One Health” approaches that would allow more comprehensive characterization of potential risks and exposure routes.\nWe highlight several factors and pathways that need to be considered when evaluating paraben exposure and the increased risk of developing estrogen-mediated cancers (Fig.  1 ). We identified life stages, biological sex/gender, ethnicity/race, geography and socioeconomics, lifestyle and dietary choices and occupation, all of which influence direct exposure (via product availability, consumer preferences) or indirect exposure (via contaminated environment, food, and water). For example, geography and socioeconomics strongly shape environmental exposure, product availability, consumption patterns, and advertisements. Geography also influences policies and regulations, which are country- or region-specific. These regulations determine daily intake limits, maximum allowed concentrations, and the type of paraben molecules in various products. For example, in the European Union (EU), several types of parabens are banned (i.e., phenyl, benzyl), and others (i.e., methyl-paraben) are only allowed in cosmetic products up to 0.4% individually or 0.8% as total parabens 13 . Conversely, in the USA, there has not been a ban on parabens in cosmetics yet based on Food and Drug Administration (FDA) regulations; however, there are limits for food items, with the maximum allowed concentration capped at 0.1% 16 . The regulations for cosmetic ingredients that contain parabens vary by country as well. For example, South Africa, which has the largest cosmetics market in Africa, aligns with the EU for the cosmetics regulation frameworks, whereas India has adopted a framework similar to the USA, including some features of the EU 17 . Fig. 1 Factors influencing exposure to parabens. Exposure patterns to paraben esters are impacted by several factors including the product availability, personal choice and indirect exposure via contaminated food, water, and environment. Policies, regulations, and demographics may mediate the exposure patterns and levels. Created in BioRender. Herbst-Kralovetz, M. (2025)  https://BioRender.com/izjjp8z .\nExposure patterns to paraben esters are impacted by several factors including the product availability, personal choice and indirect exposure via contaminated food, water, and environment. Policies, regulations, and demographics may mediate the exposure patterns and levels. Created in BioRender. Herbst-Kralovetz, M. (2025)  https://BioRender.com/izjjp8z .\nPrior research assessing paraben exposure based on cross-country analysis, through urinary measurements, reported that exposure was much greater in China and Korea than in Europe and United States 18 , indicating widely varying product use, regulations, and ultimately health effects in different geographical regions. Driven by regulatory efforts, consumer advocacy, education, research, and the influence of social media, there has been a rise in the “clean” product movement - particularly in the development of paraben-free formulations. However, replacement or substitute compounds may also possess unintended toxicological or sensitization-related effects. Therefore, the safety of alternative compounds also should be comprehensively evaluated to avoid “regrettable substitution”, where one potentially harmful compound is replaced with another insufficiently characterized alternative, as previously comprehensively reviewed 19 .\nBesides geography and socioeconomics, interpersonal differences, biological (genetics, sex), social (race/ethnicity) or behavioral (life choices) factors play a key role in determining the exposure levels, frequency, and the specific subtypes of parabens an individual is exposed to. Lifelong exposure begins during the prenatal period, and highest exposure has been predicted to occur during the reproductive years and pregnancy in women 20 . Typically, women use more PCPs, cosmetics, and hygiene products than men 21 . In line with this, product use is also associated with race/ethnicity, as non-White women might be more exposed to parabens than White women 20 , potentially due to use of hair and skincare products specific for Black and Hispanic/Latina women 22 . A recent study highlighted higher blood concentrations of parabens in women than men across various occupational categories 23 . Occupations can alter paraben exposure, with women working in the beauty industry having greater urinary concentrations of paraben esters 24  than those employed in other fields.\nGiven that inter-individual variations that are shaped by biological, social, behavioral and environmental factors greatly influence levels, types and frequency of paraben exposure, they need to be taken into account when assessing the potential link between parabens and the development of estrogen-mediated cancers. Additionally, the relative impact of direct versus indirect exposure as well as acute versus chronic exposure on cancer risk remains uncertain. Understanding these exposure patterns is critical for developing effective cancer risk-reduction strategies and assessing public health risks, as these pathways may reflect the rising trends in estrogen-mediated cancers.\nWith the advancements in the field of metabolomics, parabens have been increasingly detected in various biological fluids and tissues using both targeted and non-targeted approaches in healthy individuals 9  and cancer patients 8 , 9 , 25 , 26 . The majority of cancer studies have focused on breast cancer, highlighting a lack of data on parabens and other estrogen-mediated cancers such as ovarian and endometrial cancer.\nThe associations between cancer risk and parabens have often been established based on concentrations of paraben esters in specified biospecimens (summarized in Table  1 ), including studies reporting greater abundance or detection of parabens in cancer tissues or other samples from patients with cancer compared to controls, as well as epidemiological analyses calculating odds ratios from biospecimen measurements. These studies were mainly conducted in the USA; however, there were a few studies from Türkiye 25  or Iran 8 . In breast cancer patients, odds ratios were statistically significantly higher for urinary methyl- and butyl-paraben esters and concentrations of paraben esters were significantly greater in the malignant breast tissue versus benign breast tissue 8 . Similarly, parabens were detected in higher amounts in endometrial cancer tissue in comparison to premalignant endometrial intraepithelial neoplasia 25 . Interestingly, history of self-reported uterine cancer was inversely associated with ethyl-paraben 27 . Table 1 Detection of paraben in serum, urine, and tissue of cancer patients Cancer type Time of sampling Population size ( n ) Age [range, (average or median)] Location, race/Ethnicity Sample type Analysis method Type of paraben and concentration range The association between parabens and cancer Breast  Breast 26 ∼3.3 years before diagnosis 1032 cancer cases & 1030 age-matched controls 45–75 (post-menopausal) USA/ African American Latino Native Hawaiian Japanese American White Urine LC-HRAM-MS Average (μg/g creatinine) MeP 49.4 PrP: 18.5 EtP: 1.15 BP: 0.15 BeP: 0.004 Inverse association with total parabens: OR T3  vs  T1  = 0.77 (95%CI: 0.62–0.97), P trend  = 0.03  Breast 9 Within 3 months of diagnosis 708 cancer cases & 598 controls NA - 65 (34.2) USA/ not specified Urine HPLC-MS Total range (μg/g creatinine) MeP: (1-3174) PrP: (DL < to 3116) BP: (DL< to 173) MeP and BP associated with increased odds of breast cancer. Increased risk in hypomethylated global DNAm group (OR:1.46)  Breast 8 Newly-diagnosed 101 cancer cases & 47 benign controls 13–76 (41.5) Iran Tissue (breast) GC-MS (metastatic-benign, ng/g) MeP: (173–149) EtP: (122–102) PrP: (93–59) BP: (82–45) Significantly higher butyl and propyl ( p  = 0.001) in metastatic (cancer) vs benign (fibroadenoma) tumors  Breast 43 Diagnosed 53 cancer cases 36 non-menopausal 16 menopausal Iran Tissue (breast) Targeted GC (benign -malignant, ng/g) MeP: (164–178) EtP: (144–136) PrP: (97–99) BuP: (107–87) Total: (507–497) Positive dose response pattern for MePB ( p  < 0.001)  Breast 80 History of cancer (timing not available) 134 cancer & 4321 cases 47.52 (16.98) for healthy and 65.29 (12.84) for cancer patients USA/Mexican American, Hispanic African American Urine HPLC-MS Median (IQR, Range ng/mL) MeP: 4.86 (2.29, 3.62–5.91) EtP: 0.64 (2.94, -0.35–2.6) PrP: 3.19 (2.89, 1.55–4.44) BP: -1.61 (2.65, -1.96–0.69) No statistically significant association Endometrial / Uterine cancer  Endometrial 41 +10 years before diagnosis 139 pre-cancer cases and 139 cancer-free controls 59-69 (62) – at the time of urine collection USA/ White, African American, Native Hawaiian, Japanese American, Latina Urine HPLC tandem mass spectrometry Median creatinine normalized (control-cases) MeP: (98.73–78.64) EtP: (3.23–1.47) PrP: (20.16–11.30) BP: (0.36–0.15) Total: (137.13–11.55) No statistically significant association  Endometrial 25 Concurrent with diagnosis 33 cancer cases & 6 controls (intraepithelial neoplasia) 49–57 Türkiye Tissue (endometrial, myometrial) UHPLC-MS/MS (ng/g) MeP: < DL EtP: < DL PrP: 6.3–60.5 BeP: 9.1–22.4 IsoBP: 5.4–118.2 Higher in endometrial carcinoma tissue compared to normal endometrium ( p  = 0.02)  Uterine 27 History of cancer (timing not available) 37 cancer survivors & 3432 control >20 (48) White (non-hispanic) Black (non-hispanic) Mexican American Other Hispanic Other Urine HPLC-Tandem MS NA Higher EtP inversely associated with previous history of cancer OR:0.31, 95% CI: 0.12, 0.85\nDetection of paraben in serum, urine, and tissue of cancer patients\nUSA/ African American\nLatino\nNative Hawaiian\nJapanese American\nWhite\nAverage (μg/g creatinine)\nMeP 49.4\nPrP: 18.5\nEtP: 1.15\nBP: 0.15\nBeP: 0.004\nInverse association with total parabens:\nOR T3  vs  T1  = 0.77 (95%CI: 0.62–0.97),\nP trend  = 0.03\nTotal range (μg/g creatinine)\nMeP: (1-3174)\nPrP: (DL < to 3116)\nBP: (DL< to 173)\nMeP and BP associated with increased odds of breast cancer.\nIncreased risk in hypomethylated global DNAm group (OR:1.46)\n(metastatic-benign, ng/g)\nMeP: (173–149)\nEtP: (122–102)\nPrP: (93–59)\nBP: (82–45)\nTargeted\nGC\n(benign -malignant, ng/g)\nMeP: (164–178)\nEtP: (144–136)\nPrP: (97–99)\nBuP: (107–87)\nTotal: (507–497)\nUSA/Mexican American,\nHispanic\nAfrican American\nMedian (IQR, Range ng/mL)\nMeP: 4.86 (2.29, 3.62–5.91)\nEtP: 0.64 (2.94, -0.35–2.6)\nPrP: 3.19 (2.89, 1.55–4.44)\nBP: -1.61 (2.65, -1.96–0.69)\nMedian creatinine normalized (control-cases)\nMeP: (98.73–78.64)\nEtP: (3.23–1.47)\nPrP: (20.16–11.30)\nBP: (0.36–0.15)\nTotal: (137.13–11.55)\n(ng/g)\nMeP: < DL\nEtP: < DL\nPrP: 6.3–60.5\nBeP: 9.1–22.4\nIsoBP: 5.4–118.2\nWhite (non-hispanic)\nBlack (non-hispanic)\nMexican American\nOther Hispanic\nOther\nHigher EtP inversely associated with previous history of cancer\nOR:0.31, 95% CI: 0.12, 0.85\nParabens have also been investigated in the context of non-estrogen-mediated cancers. For example, greater concentrations of methyl, ethyl, propyl, and butyl parabens were detected in the urine of lung cancer patients than in non-cancer controls 28 . Notably, risk for lung cancer is 2.7 times higher in women than men 29 . Parabens in urine have been associated with self-reported prostate cancer 30 , thyroid cancer 31 , and previous melanoma diagnosis 27 . However, these cancers are also strongly influenced by multiple intrinsic and extrinsic risk factors, including smoking habits, genetic susceptibility, hormonal status, medication use, and other environmental exposures. Hence, parabens should be considered as one potential component within a complex network of interacting factors rather than as isolated drivers of cancer development. Even though these cancers are not widely recognized as being directly driven by estrogen signaling, parabens may also induce carcinogenic pathways via non-estrogen-dependent mechanisms. Additionally, parabens have also been detected through untargeted metabolomics in bladder and colon cancer studies 32 , 33 ; however, they have not been prominently analyzed within the context of cancer risk, as most studies focused on intrinsic metabolites. Besides cancer, parabens have been frequently associated with the pathophysiology of other gynecological and reproductive disorders (Table  2 ). For example, early menopause 34 , female infertility 35 , endometriosis 36 , fibroids 37  and ovarian aging 38  have been positively associated with at least one type of parabens. Many of these reproductive conditions, including ovarian aging and menopause, are also risk factors for estrogen-mediated cancers 39 . Table 2 Detection of paraben esters (MeP, methyl-paraben; PrP, propyl-paraben; EtP, ethyl-paraben; BP, butyl-paraben; HeP, heptyl-paraben) in urine samples of obstetric/gynecological conditions other than cancer Condition Time of sampling Population size ( n ) Age [range, (average or median)] Location, race/Ethnicity Sample type Analysis method Type of paraben and concentration range The association between parabens and the condition Ovarian aging/fertility 38 Before fertility treatment 192 21–46.7 (36.1) USA/Caucasian, African American, Asian Urine HPLC-MS (μg/L) MeP: 3-4400 PrP: <DL – 1430 BP: <DL - 142 Positive correlation between PrP and diminishing ovarian reserve ( p  = 0.007) Midlife-reproductive health outcomes 34 Not available (Premenopausal and perimenopausal women) 101 45–54 (47) USA/non-Hispanic White Urine HPLC-MS BP < EP <PrP < MP Positive association between total parabens and hot flashes, FSH, reduced ovarian volume Endometriosis 36 33 20–54 (38) Spain Urine UHPLC-MS/MS Mean (ng/mL) MeP: 236.56 EtP: 44.20 PrP: 16.43 BP: 0.81 BP and PrP positively associated with the key genes for the development and proliferation of endometriosis. Fertility 81 During the enrollment before conception 525 couples 29.2 + 3.2 China Urine Targeted HPLC-MS/MS MeP: (95.7–79.9) EtP: (1.78– 1.11) PrP: (2.6– 3.27) BP: (0.02– 0.11) HeP: LOD PrP, BP, and HeP associated with reduced fecundability and increased risk of infertility\nDetection of paraben esters (MeP, methyl-paraben; PrP, propyl-paraben; EtP, ethyl-paraben; BP, butyl-paraben; HeP, heptyl-paraben) in urine samples of obstetric/gynecological conditions other than cancer\n(μg/L)\nMeP: 3-4400\nPrP: <DL – 1430\nBP: <DL - 142\nMean (ng/mL)\nMeP: 236.56\nEtP: 44.20\nPrP: 16.43\nBP: 0.81\nMeP: (95.7–79.9)\nEtP: (1.78– 1.11)\nPrP: (2.6– 3.27)\nBP: (0.02– 0.11)\nHeP: LOD\nOur review demonstrates that our understanding of parabens in cancers, specifically estrogen-mediated cancers, is still largely limited. Therefore, there is an urgent need to characterize parabens in various biological matrices, including those reflecting localized exposure (e.g., tissues and lavages) and systemic circulation (e.g., blood, urine, and feces), across different types and stages of estrogen-mediated cancers, particularly in understudied reproductive tract organs. Additionally, banked biological samples can be evaluated to better understand exposure pathways and their relationship to cancer progression.\nAssociating parabens with cancer risk poses several challenges, including sampling time, type of sample, and heterogeneities in the populations due to the presence of several cofactors. The majority of prior research on cancer (summarized in Table  1 ) relied on the targeted detection of parabens mostly in urine or tissue either before, during, or after diagnosis, based on a measurement at a single timepoint. Time of sampling is critical for several reasons. Studies utilizing pre-diagnostic sampling primarily assess whether exposure precedes disease development, whereas studies performed at the time of diagnosis or in tumor-associated tissues mainly reflect co-occurrence within the local environment. In contrast, retrospective survivor studies may additionally reflect disease-associated behavioral, metabolic, or pharmaceutical changes following diagnosis. For example, sampling of current cancer patients suggests possible heavy medication use by the patients due to therapies which might exacerbate exposure levels, as parabens are common drug excipients. Sampling too far in advance or after diagnosis in cancer-free patients may complicate the interpretation of the relationship between exposure and cancer risk, as parabens are rapidly metabolized (<24 h) and excreted in urine 40 . To establish a more accurate association, longitudinal sampling reflecting chronic exposure history is necessary. For example, surprisingly, an inverse association between paraben exposure and breast or endometrial cancer was observed when sampling was performed in individuals before cancer development 26 , 41 . In these studies, the cancer diagnosis occurred on average 6.6 years after urine sampling in the endometrial cohort 41  and 5.5 years after in the breast cancer cohort (sampling 2001–2006 and diagnosis 2001–2014) 26 . Whereas a positive association between parabens and breast cancer, with a higher odds ratio, was observed when sampling was conducted either at the time of the diagnosis or 3 months after the diagnosis 8 , 9 .\nBiospecimen type is also crucial for studying these associations. As parabens are excreted in urine, these samples indicate daily or relatively recent exposure due to the rapid metabolism and excretion of parabens, whereas tissue-based measurements may provide insight into local accumulation or tissue-specific exposure patterns over longer durations of time. Measurement of paraben esters in the local breast cancer microenvironment revealed an interesting phenomenon: the concentration of paraben esters was statistically significantly higher in malignant tissue compared to adjacent healthy tissue 8 . This co-occurrence may reflect altered tissue metabolism, differential accumulation of paraben molecules, disease-associated changes within the tumor microenvironment, or a potential role of parabens in tumorigenesis, the mechanisms of which need to be elucidated. A pharmacokinetics study in rats revealed that oral or topical exposure to parabens leads to mainly excretion via urine (70%) or feces (4%) but also accumulation in tissues (2%) 42 .\nThe heterogeneities in exposure pathways and inter-individual variations present additional challenges in associating parabens with an increased cancer risk. For example, women with global DNA hypomethylation may have a greater risk of breast cancer when exposed to parabens. A dose-response relationship with breast cancer risk factors (e.g., ER+ and PR+) was also reported; methyl-paraben and total paraben concentrations were positively associated with these risk factors 43 . Targeted metabolomics studies that focus exclusively on parabens often overlook the influence of other potential EDCs or intrinsic factors like estrogens and the gut microbiome 44 . These factors are closely linked to activation of the nuclear receptors that parabens also target 45 . Without comprehensive metadata accounting for other confounding factors (i.e., exposure to carcinogens, estrogenic compounds, and other xenobiotics), these associations remain difficult to interpret. On the other hand, detection of parabens may potentially reflect broader environmental or lifestyle-associated exposure patterns to EDCs, although validation studies are needed. Co-exposure to other environmental and intrinsic factors should also be considered in terms of cancer risk, as they may all individually or in combination modulate carcinogenesis at multiple stages including initiation, promotion, progression, and invasion.\nParabens have been most commonly analyzed in systemic biospecimens such as plasma and urine, as well as in neoplastic tissues, while their presence within local microenvironments remains less explored. Previously, using global metabolomic approaches, we characterized the metabolome of cervicovaginal lavages from women newly diagnosed with cervical 46  and endometrial 47  cancers. This non-invasive sampling approach demonstrated that, with the available library of compounds, 12 benzoate metabolites were detectable in samples from the cervical cancer cohort and 20 benzoate metabolites in samples from the endometrial cancer cohort. The main paraben metabolite, 4-hydroxy-benzoate, was at significantly greater levels in endometrial cancer patients than those with endometrial hyperplasia (precancerous conditions) ( p  < 0.01) or benign controls ( p  < 0.0001). This metabolite was not included/detected in the cervical cancer study. However, it is important to note that 4-hydroxybenzoate can naturally occur in food, particularly berries 48 , and therefore may not exclusively reflect paraben metabolism but also dietary patterns. In both studies, methyl-4-hydroxybenzoate sulfate was detected at significantly higher levels in cancer patients compared to non-cancer controls or dysplasia/hyperplasia patients (Fig.  2 , and Supplementary Table  1 ). Methyl-hydroxybenzoate sulfate is the sulfonated form of methyl-paraben, one of the most used parabens in various products ranging from foods to PCPs. Liver metabolism by sulfatases makes methyl-paraben water soluble by adding a sulfate group, which facilitates its excretion from the body. The greater abundance of methyl-paraben sulfate in cervicovaginal lavages of cancer patients may reflect possible increased exposure or differential accumulation and is consistent with studies observing greater abundance of parabens in urine of other estrogen-mediated breast cancer patients 9 , 43 , 49 . Fig. 2 Detection of paraben esters in cervicovaginal lavages in cervical and endometrial cancer cohorts. A liver metabolite of methyl-paraben, methyl-4-hydroxybenzoate sulfate was detected at significantly greater levels in cancer patients [both endometrial (EC) and cervical (ICC)] in comparison to their relative controls. ANOVA,  * p  < 0.05,  ** p  < 0.01,  *** p  < 0.001,  **** p  < 0.00001.\nA liver metabolite of methyl-paraben, methyl-4-hydroxybenzoate sulfate was detected at significantly greater levels in cancer patients [both endometrial (EC) and cervical (ICC)] in comparison to their relative controls. ANOVA,  * p  < 0.05,  ** p  < 0.01,  *** p  < 0.001,  **** p  < 0.00001.\nWe also correlated relative levels of methyl-4-hydroxybenzoate sulfate with other metabolites detected in the cervicovaginal lavages, including other xenobiotics. This analysis was performed because parabens may be present as excipients in certain medications, and medication use patterns may differ between healthy individuals and cancer patients. In the cervical cancer cohort, methyl-4-hydroxybenzoate sulfate strongly correlated with the parent molecule 4-hydroxybenzoate and metabolite phenol sulfate (Spearman’s ρ = 0.88, and 0.81, respectively). It also correlated with several carnitine metabolites (i.e., myristoylcarnitine (Spearman’s ρ = 0.86), laurylcarnitine (Spearman’s ρ = 0.83), which were metabolic signatures of cervical cancer 46 , but also with a particular pharmaceutical, naproxen (Spearman’s ρ = 0.73) and its liver metabolite desmethyl-naproxen sulfate (Spearman’s ρ =0.71). Naproxen formulations, particularly oral suspensions, contain methyl-paraben to extend shelf-life. The same analysis on the endometrial cancer study demonstrated a weak correlation between naproxen and methyl-4-hydroxybenzoate (Spearman’s ρ =0.14). The differences observed between the two cohorts could potentially be due to differences in their respective control groups; the cervical cohort included individuals with no apparent health conditions, whereas the endometrial cohort controls consisted of individuals with benign gynecological conditions. Overall, our data demonstrated the presence of parabens (and/or their liver-transformed metabolites) in the local cervicovaginal microenvironment of patients recently diagnosed with cervical or endometrial cancer, expanding previous findings that were largely limited to measurements in systemic matrices such as blood, urine, and other peripheral biospecimens. As demonstrated by our analysis, examining the correlation between drug use and hepatic metabolism of parabens highlights the importance of considering pharmaceutical-associated exposure when evaluating potential biomarkers.\nTo investigate the causative role of paraben exposure on the etiology of estrogen-mediated cancers, several cell culture models have been repurposed or developed. These experimental models provide different levels of biological and translational insights. Immortalized cell lines are useful for investigating molecular pathways under controlled conditions; primary human cells may better reflect human tissue physiology; and animal models provide organism-level evidence but do not fully recapitulate human exposure patterns, hormonal environments, or gynecologic cancer biology. Similar to the findings from clinical or observational studies, the majority of these models have focused on breast cancer, predominantly using human epithelial mammary gland cell lines. These cell lines were estrogen-receptor (ER) positive or negative and mainly derived from tissues collected from White women, thus not representing ethnic and/or genetic diversity among women. While the majority of the cell lines were immortalized, several studies also included primary cells from women undergoing breast surgery, some derived from Black women 11 , 50 .\nWe reviewed several hallmarks of cancer described by Hanahan and Weinberg 51  including, sustaining proliferative signaling, deregulating cellular metabolism, resisting cell death, activating invasion and metastasis, evading growth suppressors, tumor proliferating inflammation, and genome instability and mutation, to better understand the mechanisms by which parabens could be influencing carcinogenesis (Fig.  3A ). These mechanisms can be impacted through estrogen receptor signaling 52  or via independent mechanisms. Among the hallmarks of cancer, paraben esters induced apoptosis evasion 53  in a dose-dependent manner 54 ; however, transcriptomic profiling also indicated that parabens upregulated pro-apoptotic genes 54 , 55  in the immortalized MCF-10A cell line. There was also evidence of genotoxicity; for example, propyl-paraben was shown to induce DNA damage in both immortalized MCF7 and T47D breast tumor epithelial cell lines 56 . Interestingly, parabens did not seem to induce cytokine production or other inflammatory markers in the tested epithelial cell lines (both primary and immortalized), although these in vitro studies did not test cytokine production by immune cells following exposure to parabens. However, reduced ROS stress with methyl-paraben 57  linked to tumor-promoting inflammation in primary breast cancer cells has been observed. Long-term exposure (=17 days) to parabens contributed to migration and anchorage-independent growth in immortalized MCF-10A mammary gland tumor cell lines 58 , representing activation of invasion and metastasis. Parabens impacted several metabolic pathways associated with deregulating cellular metabolism, such as increased glycolysis, mTOR pathway, autophagy, and mitochondrial dysfunction in either primary or immortalized cell lines 55 , 57 , 59 , 60 . Estrogen-driven proliferation and MAPK pathway activation contributing to sustaining the proliferative signaling hallmark were also reported to be activated by various paraben esters 60 – 63 . Similar to epidemiological studies, the data on parabens and cellular models of gynecological cancers were severely limited. However, studies on primary human granulosa cell models demonstrated that parabens impaired cell growth and mitochondrial function 64 , indicating that paraben exposure may contribute to hallmarks of ovarian cancer, and these experimental findings support mechanistic plausibility. Fig. 3 Parabens and hallmarks of cancer in estrogen-mediated cancers. In-vitro ( A ) and in-vivo ( B ) models highlight various mechanisms involved in carcinogenesis of estrogen-mediated cancers in the context of paraben exposures and the outcomes of those on breast and reproductive organs.  Created in BioRender. Herbst-Kralovetz, M. (2025) \n https://BioRender.com/rp91efg .\nIn-vitro ( A ) and in-vivo ( B ) models highlight various mechanisms involved in carcinogenesis of estrogen-mediated cancers in the context of paraben exposures and the outcomes of those on breast and reproductive organs.  Created in BioRender. Herbst-Kralovetz, M. (2025) \n https://BioRender.com/rp91efg .\nBesides the reproductive and breast cell models, interactions between parabens and immune cells have been investigated under in vitro conditions, given that immune dysregulation and chronic inflammation are well-established hallmarks and enabling characteristics of cancer. For example, at physiologically relevant concentrations, five common paraben esters exhibited immunotoxic effects on macrophages by increasing phagocytosis while dampening chemotaxis and secretion of major pro-inflammatory cytokines (TNF-α and IL-6) as well as anti-inflammatory IL-10 65 . Similarly, neutrophils isolated from human donors that were exposed to methyl-paraben demonstrated reduced phagocytic capacity, chemotaxis, and superoxide amine production 66 , suggesting altered innate immune responses and impaired immune surveillance. In parallel, parabens enhanced retinoic acid-related orphan receptor γt-dependent transcription of pro-inflammatory IL-17A and IL-22 genes in a murine Th17 cell model 67 , indicating potential modulation of inflammatory T-cell pathways. These interactions suggest that parabens may influence immune pathways relevant to tumor-promoting inflammation and immune regulation; however, the implications for carcinogenesis remain unclear, as activation or suppression of different immune cell populations may exert both tumor-promoting and tumor-suppressive effects depending on the biological context and stage of the disease.\nParabens generally exhibit weaker estrogenic activity and receptor affinity compared to endogenous estradiol 68 , suggesting that their biological effects may be more subtle and context-dependent, particularly in single-exposure studies. However, experimental studies investigating the mechanistic and endocrine-disrupting effects of parabens often employ exposure conditions designed to evaluate molecular pathways and biological responses under controlled settings rather than directly replicating typical human exposure scenarios. At the same time, several studies have examined either long-term exposures (>20 weeks) or a broad concentration range (0.2 nM–10 μM), including physiologically relevant doses (0.2 nM) in breast cancer cell lines 54 , 69 , 70 . While these in vitro experimental models provide valuable mechanistic insights into the biological activity of parabens, their translational relevance to chronic human exPposure and cancer risk remains to be fully established.\nAnimal models (mouse and rat) provided mechanistic evidence between paraben exposure and ovarian follicle or mammary gland health (Fig.  3B ). For example, various paraben esters led to increased growth of mammary gland cancer and disruption of ovarian basal follicular cell function or folliculogenesis 71 , 72 . These findings were consistent across all animal models (C57BL/6J, BDF1 mice or Sprague-Dawley rats) 56 , 68 , 73 , 74 , supporting the outcomes of mechanisms observed from in-vitro cell culture models. Additionally, propyl-paraben disrupted the estrous cycle and reduced oocyte number in BALB/c mice 75 . Whereas prenatal exposure to propyl-paraben induced similar effects on the offspring by disrupting steroidogenesis and accelerated ovarian aging in C57BL/6J mice 76 . Similarly, prepubertal exposure to butyl-paraben led to oxidative stress, disruption of steroidogenesis, and an increase in gonadal weight in Swiss Webster albino mice 77 . These findings highlight that the biological effects of parabens depend on dose, duration, and ester-type. These effects may vary substantially depending on exposure conditions and experimental context. In parallel, findings from developmental and reproductive toxicity studies remain heterogeneous across experimental systems and exposure conditions. While several studies reported endocrine, reproductive, or mammary gland alterations following paraben exposure, other standardized toxicological and multigenerational studies reported limited or no significant adverse reproductive or developmental outcomes 78 , 79 . Overall, in-vitro and animal models have provided preliminary evidence that paraben exposure can alter cellular function, contribute to hallmarks of cancer and deteriorate organ health. However, findings from experimental models should be interpreted cautiously and may not fully recapitulate human disease biology and exposure patterns.\n\nEmerging evidence suggests a possible association between increased paraben exposure and the occurrence of several estrogen-mediated cancers. However, large gaps in the data hinder definitive conclusions. It remains unclear whether high levels of parabens observed in cancer patients are coincidental—reflecting greater exposure to various endocrine disruptors as exposures occur as cocktails rather than individual compounds—or if they indicate a causal relationship driven by the estrogenic activity of parabens. We highlight several steps that could be taken to move from correlation to causation (Box  1 ).\nFinally, although there are country/region-specific regulations on certain paraben molecules, their widespread production and use remain a global concern. Considering these molecules accumulate in water and soil, meaning their impact on human health extends beyond direct exposure to indirect exposure, is concerning. Strengthening and clarifying the association between paraben exposure and estrogen-mediated cancers will reinforce the need for stricter regulations to limit their inclusion in products as preservatives and encourage the search for safe alternatives. Eventually, it will help consumers make more informed choices, such as opting for drugs, cosmetics, and food items that are paraben-free. Deepening our understanding of how parabens and other endocrine disruptors influence gynecologic and estrogen-mediated cancers is a critical step towards advancing women’s health on a global scale.\nScreening larger and more diverse populations, conducting longitudinal studies and establishing biobanks of samples from different biological samples or organs. Longitudinal studies will enable multiple time-point sampling, helping to identify the optimal timing for diagnosis. Tracking exposure sources, patterns and frequency of potential environmental exposures in populations prior to cancer diagnosis and throughout treatment. Expanding untargeted metabolomic libraries to include a broader range of environmental contaminants, and developing standardized protocols for analyzing various biological specimens. Developing personalized or organ-specific models that represent different life stages (for example, prenatal, reproductive age, peri-menopausal or post-menopausal) to relate clinical observations and elucidate underlying mechanisms in humans. Investigating estrogen-related mechanisms including parabens’ interactions with estrogen receptors, pathways as well as independent mechanisms in the development and progression of tumorigenesis, and bioaccumulation mechanisms in the cancer tissues. Incorporating exposure pathways (for example, geography or lifestyle choices), timing and dosing response schemes, including acute versus chronic exposures.\nScreening larger and more diverse populations, conducting longitudinal studies and establishing biobanks of samples from different biological samples or organs. Longitudinal studies will enable multiple time-point sampling, helping to identify the optimal timing for diagnosis.\nTracking exposure sources, patterns and frequency of potential environmental exposures in populations prior to cancer diagnosis and throughout treatment.\nExpanding untargeted metabolomic libraries to include a broader range of environmental contaminants, and developing standardized protocols for analyzing various biological specimens.\nDeveloping personalized or organ-specific models that represent different life stages (for example, prenatal, reproductive age, peri-menopausal or post-menopausal) to relate clinical observations and elucidate underlying mechanisms in humans.\nInvestigating estrogen-related mechanisms including parabens’ interactions with estrogen receptors, pathways as well as independent mechanisms in the development and progression of tumorigenesis, and bioaccumulation mechanisms in the cancer tissues.\nIncorporating exposure pathways (for example, geography or lifestyle choices), timing and dosing response schemes, including acute versus chronic exposures.\n\nPubMed, SCOPUS, Web of Science, and Embase databases were searched. Additionally, Google Scholar was utilized. Our search terms included combinations of “paraben”, “benzoate”, “endocrine-disrupting compounds”, “estrogen-mediated cancer”, “metabolomics”, “breast cancer”, “endometrial cancer”, “ovarian cancer” and “cervical cancer”. Searches were performed between January 2025 and July 2025.\nOnly articles published in English were considered in this review. Both targeted and untargeted studies were included. Eligible studies comprised observational studies in humans, mechanistic studies using cell culture models (originated from primary or immortalized breast, ovarian, endometrial and cervical cell lines), and experimental studies in animal models. Studies unrelated to cancer, endocrine disruption-related disorders, or paraben-associated mechanisms were excluded unless discussed for contextual relevance. For clinical and epidemiological studies, we extracted information on study design, population characteristics, sample size, biological matrix analyzed, paraben type measured, and analytical method, and key outcomes. For cell culture models or experimental studies, we recorded paraben ester type, model system, study duration and endpoints assessed. Studies were selected based on relevance to the scope of the review and their contribution to understanding exposure, co-occurrence with disease, mechanisms, and evidence approaching causality aspects.\nGlobal metabolome data from previously published metabolomic studies on cervical (10 cancer patients and 68 controls including 29 without and 39 with dysplasia) 46  and endometrial (66 cancer patients and 126 controls including 108 without and 18 with hyperplasia) 47  cancers were used for an exploratory secondary analysis focused on paraben metabolites. Briefly, in these studies, cervicovaginal lavages (CVL) samples were collected from women who were newly diagnosed with cervical or endometrial cancer and respective control groups, including benign conditions, pre-cancerous lesions, and women with no dysplasia/hyperplasia. Samples were collected from participants who were newly diagnosed with gynecologic cancer prior to any treatment. Untargeted metabolomics was previously performed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) as described in detail in the original studies. Metabolite annotations were based on comparison to Metabolon’s authenticated reference library of purified standards, with parameters including retention index, mass-to-charge ratio, and MS/MS spectral matching.\nParaben metabolites were selected a priori as a chemically defined class; relative abundances of 12 benzoate metabolites in the cervical cancer dataset and 20 metabolites in the endometrial cancer dataset were evaluated. Statistical comparisons of metabolite levels across clinical groups were performed using ANOVA, followed by Tukey’s post-hoc test for pairwise comparisons, and significance thresholds were set at  p  < 0.05. Given the small number of pre-specified comparisons and the hypothesis-driven nature of this secondary analysis,  p  values are reported without correction for multiple comparisons. To investigate potential links between paraben metabolites and other detected metabolites, including xenobiotics and pharmaceutical compounds, Spearman’s correlation analysis was conducted. Medication use was inferred from the detected pharmaceuticals in the CVL samples. All analysis were performed using the GraphPad Prism 10 software.\n\nSupplementary_Table_1.\nSupplementary_Table_1.","source_license":"CC-BY-4.0","license_restricted":false}