Urinary phenols and parabens exposure in relation to urinary incontinence in the US population

Urinary incontinence (UI) is characterized by the involuntary loss of urine, resulting in an individual's inability to control the timing and amount of urine expelled. According to Irwin et al., approximately 13.1% of women and 5.4% of men have experienced UI [1]. Furthermore, persistent UI significantly impacts the quality of life. Gibson's research reveals that elderly women with incontinence have a 1.5 to 2.3-fold higher risk of falls, contributing to increased overall morbidity, mortality, and healthcare expenditure [2]. These findings highlight UI as a prevalent issue with profound implications for health-related quality of life in the general population.

The intricate nature of UI emphasizes the pivotal role of pelvic floor integrity in its pathogenesis, which involves factors such as detrusor overactivity, poor detrusor compliance, bladder hypersensitivity, and urethral hypermobility [3]. Research indicates that menopausal women with SUI exhibit reduced estrogen receptors in the periurethral fascia. Hormonal shifts among SUI patients alter extracellular matrix components, contributing to SUI by affecting tissue architecture and mechanical attributes [4, 5]. Additionally, ongoing urothelial irritation due to local immuno-inflammatory responses can contribute to urinary incontinence [3]. This implies that changes in the endocrine state and inflammation can impact pelvic floor tissue structure, leading to urinary dysfunction. Besides, environmental factors, such as organophosphate esters with known endocrine-disrupting properties, are also linked to structural disruptions in the pelvic floor, contributing to incontinence [6].

Daily use of PCPs exposes individuals to environmental pollutants, including triclosan (TCS), benzophenone-3 (BP-3), bisphenol A (BPA), and parabens (PBs). Benzophenone-3 is primarily sourced from UV filters in sunscreen formulations and many other consumer products [7]. Furthermore, Pycke et al. [8] suggest that TCS exposure primarily occurs through the topical application of PCPs, dermal contact with consumer products, and toothpaste ingestion, representing a significant exposure route for human populations. PBs, a group of alkyl esters (e.g., methyl, ethyl, propyl, butyl) of hydroxybenzoic acid, are widely employed as antimicrobial preservatives in personal care items, and studies have identified PCPs as significant sources of PBs exposure [9]. BPA is integral to the manufacture of polycarbonate plastics and epoxy resins [10]. While exposure from PCPs may be minimal, we encapsulate the entirety under the term "personal care products related phenols" for a comprehensive analysis of PCPs-related substances.

These compounds, known for their potential bioactive effects, may contribute to diseases by disrupting normal biological processes [3]. Notably, as endocrine disruptors, TCS and parabens hinder human aromatase activity, reducing estrogen production [11]. BPA's strong interaction with estrogen receptors (ER) is recognized to impair ER functionality [12]. An in-depth analysis of BP-3 suggests that its highest internal concentrations, attained after a single application of commercially available sunscreen (4% w/w), align with concentrations causing endocrine-disrupting effects in vitro and adverse effects on female reproduction in rodents in vivo [13]. Beyond endocrine disruption, Aung et al. [14] found inverse relationships between maternal plasma inflammatory markers and urinary PNs and PBs levels, and Watkins et al. [15] identified a significant link between elevated urinary BPA and parabens levels and increased oxidative stress indicators. Long-term exposure to bisphenol A in mice was associated with urothelium impact, resulting in increased prostatic ducts and reduced urethra lumen size [16].

Considering the potential implications of the mentioned PNs and PBs on pathways related to UI, exposure to these environmental pollutants may adversely affect pelvic tissues. Our study is the first to explore the biological impact of PCPs-related substances on pelvic floor diseases. Through demographic data analysis, we aim to illuminate pelvic floor structural disorders and environmental influences, providing valuable clinical evidence and suggesting innovative treatment strategies.

We adhere to the NHANES Survey Methods and Analytic Guidelines for data collection and processing, available at https://​wwwn.​cdc.​gov/​nchs/​nhanes/​analyticguidelin​es.​aspx.

We present evidence for the significantly higher concentration of BP3 among patients with SUI. Aoki et al.'s work [3] underscores the pivotal role of urethral hypermobility and urinary sphincter weakness in the pathogenesis of SUI, attributing urethral hyperactivity to the loss of support caused by weakened endopelvic fascia and muscles during episodes of abdominal pressure. Notably, sex steroid hormones exert a profound influence over pelvic muscle and connective tissue synthesis and metabolism [19], suggesting that BP3's potential to disrupt pelvic floor muscle function might result from the modulation of hormone dynamics. However, postmenopausal women participating in human studies do not show significant associations between urinary BP-3 concentration and reproductive hormone levels, including estradiol, progesterone, follicle-stimulating hormone, and luteinizing hormone [20]. Furthermore, reports indicate decreased plasma testosterone levels after applying BP-3-containing creams to both adolescents and adults [21]. Mammadov et al.'s findings [22] corroborate the notion of pelvic floor muscle atrophy improvement following testosterone administration in SUI models, suggesting testosterone's anabolic effect on pelvic floor muscles. This aligns with Bhasin et al.'s observations [23] of androgens enhancing the strength of almost all striated muscles, including the levator ani muscle crucial for pelvic floor support. As both endogenous and exogenous androgens bolster pelvic floor function, BP3's disruption of testosterone function could potentially increase SUI risk. Additionally, neurogenic damage may underlie urinary sphincter functional decline. Wnuk et al.'s work [24] also highlights BP3's potential to alter receptor expression and impede necessary nervous system functions, thus implicating the long-term accumulation of BP-3 in SUI pathogenesis through neural interference. Collectively, BP3's interplay with hormonal dynamics and neurologic integrity could contribute to SUI etiology.

Research demonstrates a positive relationship between urinary BPA levels and increased probabilities of both UUI and MUI. Notably, the association between BPA exposure and increased MUI risk persists in the female demographic. UUI, characterized by detrusor muscle overactivity, leads to involuntary urine leakage. Mice exposed to BPA exhibit voiding dysfunction, marked by urethral histological changes and exacerbated non-voiding contractions due to detrusor instability [16]. This offers evidence of BPA's potential to impair detrusor function and contribute to UUI development. Doumouchtsis et al.'s review [25] underscores the intimate connection between obesity and urinary incontinence, advocating weight loss for its mitigation. A comprehensive meta-analysis across ten studies reveals a dose–response relationship between BPA exposure and the risk of obesity, indicating that a 1 ng/mL increase in BPA correlates with an 11% rise in obesity risk [26]. This implies that BPA may contribute to obesity, eventually leading to urinary incontinence in the general population. Moreover, chronic abdominal pressure, a hallmark of obesity, could compromise the pelvic floor. Furthermore, adipose tissues releasing oxidative stress factors may contribute to the degradation of pelvic floor structures [25]. Notably, MUI is diagnosed based on the co-occurrence of UUI and SUI. Although our study reveals BPA's association with UUI and MUI, the lack of association with SUI suggests a complex interplay underlying MUI, beyond a mere summation of UUI and SUI mechanisms. This emphasizes the need for further exploration to unveil the intricate determinants of MUI development.

Interestingly, heightened TCS exposure seems inversely linked to MUI occurrence in the general population. First, TCS exposure closely correlates with increased production of reactive oxygen species (ROS) in humans [27]. Prolonged ROS accumulation is linked to tissue and organ inflammation, indicating a potential avenue. Aoki et al.'s review [3] emphasizes persistent urothelial irritation from oxidative stress as a central mediator of bladder overactivity, supporting the role of ROS. Second, earlier studies [28] describe a simultaneous reduction in BMI with increased urinary TCS concentrations. As obesity has the potential to compromise pelvic floor muscles and diminish pelvic viscera support [25], TCS's impact on BMI might contribute to its effect on MUI. Meanwhile, incontinent postmenopausal women exhibit significantly lower serum Δ4-androstenedione levels and androgen receptors, which are commonly verified by biopsies from the bladder neck, and urethra compared to control subjects [29, 30]. In vitro experimentation by Christen et al. [31] illuminates augmenting dihydrotestosterone response within limited concentrations in MDA-kb2 cells co-treated with dihydrotestosterone and TCS. This suggests that TCS's dose-dependent androgen receptor agonism may contribute to enhancing androgen activity in pelvic floor muscles, potentially protecting against urinary incontinence. Additionally, TCS's impact on calcium signaling, evident in increased cytosolic calcium levels in resting myotubes [32], suggests potential roles in regulating muscle function. In aggregate, these factors collectively propose TCS's multifaceted engagement in MUI modulation.

Our study did not find a clear association between paraben exposure and any form of UI. Similar to other Endocrine Disrupting Compounds (EDCs), parabens interfere with sex hormone function and aromatase activity [33, 34]. In a cohort study [33], a correlation is established between elevated paraben levels and reduced estradiol levels. Nevertheless, Nowak et al. [35] highlight inconsistencies between animal models and human studies regarding paraben effects on the endocrine system. This is attributed to exceptionally high experimental doses in animals, leading to unreliable extrapolations of human outcomes. Kim et al.'s findings [36] suggest a significant concentration disparity between animal and in vitro studies, and actual human tissue measurements. Moreover, analysis of the Canadian Health Measures Survey [36] reveals a gender-dependent association between parabens and obesity, particularly in females, hinting at metabolic and sex hormone disparities in paraben exposure outcomes. In summary, it seems that paraben concentrations in humans may be insufficient to cause UI, despite their potential to disrupt the endocrine system.

BKMR models pinpointed urinary BPA, BP3, and TCS as the primary contributors to the overall effect. However, the impact on UI seems to vary at different concentrations, showing a slight deviation from the results of the regression analysis. This implies that comprehending the counteracting effects among exposures is crucial when evaluating the impact of mixtures on UI. This underscores that examining only one factor in isolation is insufficient for understanding the fundamental pathogenesis. It emphasizes the necessity for additional basic research to explore the combined effects of common substances on the same signaling pathway [37].

Our investigation reveals the potential involvement of BPA, TCS, and BP3 in the pathogenesis of urinary incontinence through mechanisms such as hormonal imbalance, inflammation, oxidative stress, and obesity. However, due to concentration disparities between in vitro and human studies, parabens' association with UI appears limited. These findings highlight the need for comprehensive research to enhance diagnostic precision, treatment strategies, and quality of life for urinary incontinence patients. Further investigations are warranted to provide nuanced insights into the complex landscape of UI etiology and progression.

Naturally, there are also some limitations. Our cross-sectional study doesn't establish causation; the observed associations may not imply a cause-and-effect relationship. Reverse causality, where outcomes influence exposures, is possible. Relying on self-reported patient data for diagnosing urinary incontinence may introduce misdiagnosis and recall bias. Unaccounted factors like pelvic surgery and urinary tract infections in the multifaceted nature of urinary incontinence could potentially influence our adjusted model. Limited information on personal care product usage frequency hinders exploring associations with urinary incontinence outcomes. Lastly, the rapid metabolism of PNs and PBs in the body poses a limitation, as our single sampling instance may not fully capture their long-term effects, which can vary over time.

In summary, our study revealed significant associations between UI and certain compounds in US adults. Specifically, we found positive associations with urinary BPA and BP-3 levels, while urinary TCS showed an inverse correlation. However, urinary parabens did not show significant associations with UI. The observational nature of our study necessitates caution in drawing causal conclusions. Future research using prospective study designs is crucial to validate our findings and deepen our understanding of the mechanisms linking PNs and PBs to UI, providing a more comprehensive insight into these complex associations.