The present cross-sectional, population-based analysis based on a nationally representative sample of general adults from NHANES evidenced positive associations between phthalate exposure and urinary incontinence. Specifically, it was found that a one-unit increase in log-transformed phthalates MNCP, MiBP, MBP and MCPP in participants, could have a higher likelihood of UI. Moreover, a higher level of phthalate exposure displayed a higher incidence of UI in comparison with those in the lowest tertile after multivariable adjustment. Importantly, our study was the first study that considered the relationship between exposure to phthalates and UI in general adults.
The underlying mechanisms involved in increasing risk of UI by phthalate exposure had not been unraveled. As described in previous studies, phthalate exposure may have an effect on inflammation and oxidative stress. For example, Nishioka et al.(Nishioka, et al. 2012) reported that DEHP stimulated macrophages to express inflammatory cytokines and chemokines that exacerbating their inflammatory response. Mono(2-ethylhexyl) phthalate (MEHP) was found to increase the production of IL-8 in adult neutrophils and IL-1β in neonatal neutrophils(Vetrano, et al. 2010). Furthermore, within animals, DEHP could rapidly activate NADPH oxidase and nuclear factor-kB (NF-kB) in the liver, resulting in the production of cytokines and TNFα(Rusyn, et al. 2001). And di-n-butyl phthalate (DBP) exhibited cell apoptosis induction effects by infection-induced oxidative stress in testes(Kasahara, et al. 2002; Zhou, et al. 2010). Taken together, these studies provide evidences that phthalate exposure leads to UI that is potentially mediated through oxidative stress and inflammation. Inflammation plays a key role in the process of UI (stress UI or urgency UI). Long-term inflammation could lead to bladder fibrosis, reduce bladder compliance, decrease the functional capacity of the bladder progressively and increase intravesical pressure, ultimately results in the occurrence of UI. Excessive production of reactive oxygen species (ROS) can lead to oxidative damage, leading to cell apoptosis(Jia, et al. 2015). Additionally, persistent inflammation and oxidative stress could lead to persistent urothelium irritation, which might be the crucial factor for promoting bladder overactivity(Li, et al. 2011).
The association between phthalate exposure and UI might be explained by depression and obesity. Phthalate exposure was associated with depression-like behavior in adult mice(Zuo, et al. 2014). In addition, it has been reported previously that MCPP, MCNP and MBP exposure were positively correlated with the risk of depression(Kim, et al. 2016). Some studies have accounted for the association between phthalate exposure and obesity, although the results are controversial. Specifically, there is a positive association between urinary low molecular weight (LMW) phthalates metabolites and rate of obesity. While urinary high molecular weight (HMW) phthalates and DEHP phthalate exposure are associated with higher OR for obesity in male adults (more than or equal to 60 years old) (Buser, et al. 2014; Trasande, et al. 2013). Notably, depression and obesity can cause chronic damage to the pelvic floor muscles and diminish the effect on supporting pelvic viscera. This identifies them as a factor in the pathogenesis of SUI(Bart, et al. 2008; Moser, et al. 2018; Treister-Goltzman and Peleg 2018). This might be an explanation for the higher OR of UI in individuals exposed to MCPP, MCNP and MBP. Indeed, in our subgroup analysis, we found that MCNP and MBP exposure were positive associated with the incidence of SUI.
Previous studies confirmed that phthalate exposure has an antiandrogenic effect(Radke, et al. 2018; Swan 2006; Swan, et al. 2015) and was associated with lower testosterone in male animals and humans(Botelho, et al. 2009; Meeker and Ferguson 2014). Data from NHANES, 2013–2016 demonstrated HMW phthalates could reduce the level of total, free and bioavailable testosterone among men aged ≥ 60(Woodward, et al. 2020). For menopausal women, DEHP exposure was associated with lower bioavailable testosterone and estradiol concentrations(Long, et al. 2021). A study done by Kim et al.(Kim and Kreydin 2018), found that low levels of serum testosterone increase of the risk of SUI and mixed UI in women, and the underlying mechanism may be through androgens receptor to affect pelvic musculature. Likewise, urethral tissue contains estrogen receptors, and the decrease of estrogen is related to laxity of urethral sphincter and ligament, which results in a high incidence of SUI(Adamiak-Godlewska, et al. 2018; Aoki, et al. 2017). Thus, exposure to phthalates may lead to UI by affecting testosterone and estradiol concentrations. In brief, phthalate exposure has been found to participate in UI development by affecting multifaceted etiology.
The following are the key strengths of the present study. This is the first report on the association between phthalate exposure and UI. A nationally representative sample was used for analyses. Therefore, the present results might be generalizable to the entire population of US adults. Strict quality control procedures were performed to analyze 7 urinary phthalate metabolites. Moreover, to get more accurate results, regressions were adjusted for the main potential confounders, including age, race/ethnicity, BMI, education level, comorbidity index, etc. Uniquely, our study took into account the difference between the sexes in terms of UI occurrence, and the analyses stratified for sex indicate that male and female exposure to phthalate can result in the different prevalence of UI. We also considered the association between phthalate exposure and different types of UI.
There are some limitations in our study. Firstly, since the overall study design is a cross-sectional study, no causal relationships could be deduced. We have adjusted possible confounders. Nevertheless, residual confounding remains a possibility. Second, with four years (2003–2004 and 2005–2006) of NHANES data involved phthalate exposure and UI at the same time, the sample size analyzed in this study was sufficient. Third, concentrations of phthalate metabolites were detected from spot urine samples instead of 24-hour urine samples, which may not take into account potential changes of phthalate within-person over time. Nevertheless, a single measurement of urine may be representative in the long term, although phthalate metabolites have a short half-life. Last but not least, the questionnaire interview on UI is not a diagnostic tool, but it is a valid and reliable tool for identifying UI.