Association of phthalate metabolites with periodontitis: a population-based study

The high prevalence of periodontitis has turned into a major public health issue, burdening the entire world [1, 2]. Notably, periodontitis is known to share a bidirectional relationship with various systemic conditions, suggesting that treating periodontal problems may promote overall health [3, 4]. In recent decades, fundamental research on periodontitis has progressively shed light on the pathogenesis of periodontitis. Current understandings of host-microbe interactions implicate genetics, epigenetics, lifestyle choices, and environmental influences to be critical variables in the onset and progression of periodontitis [5]. Specifically, the establishment of feedforward loops between dysbiosis within complex microbial communities and heightened host inflammatory reactions appear to significantly contribute to the progression of periodontitis [6].

Among environmental contributors, endocrine-disrupting compounds (EDCs) are known to impact human health by altering epigenetic mechanisms [7]. Phthalates, one of the common EDCs, are extensively used in a myriad of products, such as medical supplies, personal care items, food packaging, cosmetics, paints, and toys [8]. Phthalates can be ingested, inhaled, absorbed through the skin, or administered during medical procedures [9]. Existing studies have linked phthalate exposure to numerous health issues, including endocrine system dysfunction, metabolic disorders, infertility, neurologic disorders, respiratory diseases, and cancer [10‐12]. The oral cavity, which serves as a common channel of the respiratory and digestive systems, is also susceptible to phthalate exposure. It is questionable whether periodontitis is also associated with phthalate.

A prior study indicated a notable link between mono-n-methyl phthalate and periodontitis [13]. However, the underlying mechanisms are not yet fully understood. The interaction between them may be multi-faceted, involving complex biological processes such as the body's immune-inflammatory responses and oxidative stress [14‐16].

Considering the known association of phthalates with various disorders, and given the shared risk factors between periodontitis and systemic diseases [17, 18], we hypothesized that phthalates might be linked to periodontitis. This hypothesis aligns with current understandings of the multifactorial nature of periodontitis, involving both systemic health and environmental exposures. Given the relatively stable presence of phthalate metabolites in the urine across extended periods, they are reliable biomarkers for assessing phthalate exposure [19]. Hence, using cross-sectional data from the National Health and Nutrition Examination Survey (NHANES), we sought to investigate the potential association of urinary phthalate metabolites with periodontitis.

In this study, individuals with periodontitis exhibited higher levels of MECPP, MnBP, MEP, MEHHP, MEOHP, and MBzP when compared to those without periodontitis. Moreover, we observed a positive association between log-transformed MECPP, MnBP, MEHHP, MiBP, MEOHP, and MBzP and periodontitis, after adjusting for factors. It is important to note that the potential link between phthalate metabolites and periodontitis involves complex biological mechanisms that are not yet fully understood.

Research exploring the link between phthalates and periodontitis is limited. A previous study using NHANES data from 1999 to 2004 investigated the relationship between 156 environmental factors and periodontitis [13]. It reported that among current smokers, every one-point increase in the log-transformed level of mono-n-methyl phthalate was associated with a 47% increase in the likelihood of periodontitis (95% CI: 1.13–1.92) after adjusting for variables such as age, sex, race/ethnicity, socioeconomic status, and number of teeth. However, mono-n-methyl phthalate was included in the NHANES 2009–2010 and 2011–2012 cycles but was absent from the 2013–2014 cycle, and hence was not examined in our research. Instead, our study expanded the scope to include an additional 10 phthalate metabolites. By doing so, we conducted a more thorough analysis that encompassed multiple indicators, significantly enhancing the reliability of our findings. The observed pattern of consistent association between various phthalate metabolites and periodontitis underscores the potential biological effects these chemicals have in promoting such conditions. Given the ubiquity of phthalates in the environment, even a marginal increase in periodontitis risk could significantly affect public health. It is worth noting that the potential harm of phthalate metabolites may vary depending on factors such as individual differences, exposure time, pathways, and mixtures. As such, there is currently no clear consensus on safety thresholds for phthalate metabolites in urine.

Phthalates are categorized based on carbon chain length into low molecular weight (LMW) and high molecular weight (HMW) phthalates. MEHP, MECPP, MEHHP, and MEOHP are primary metabolites of di (2-ethylhexyl) phthalate (DEHP), a common HMW phthalate. phthalates are becoming increasingly prevalent due to their extensive application, thus elevating the risk of human exposure to these chemicals. The oral cavity, being a channel for both the respiratory and digestive systems, may be exposed to phthalates through various means. Phthalate metabolites have been detected in human saliva, though at lower levels than in serum and urine [27, 28].

Park et al. suggested that DEHP may reduce estrogen receptor alpha (ERα) activity [29]. Estrogens, as sex steroids, play a critical role in modulating the host immune response and maintaining bone homeostasis [30]. Notably, estrogen's influence extends beyond female bone turnover to encompass male bone metabolism as well [31, 32]. For instance, estrogen deficiency has been implicated in the onset of osteoporosis in elderly men [33]. Animal experiments have indicated that estrogen deficiency can exacerbate periodontal bone loss in rats with ligature-induced periodontitis [34, 35]. This leads us to speculate that phthalate metabolites might impact the progression of periodontitis by interfering with estrogen functions.

Previous research has indicated that chronic inflammation might act as a mediator in the link between Mono (2-ethylhexyl) phthalate (MEHP) exposure and the onset of depressive symptoms [36]. Specifically, the mediating effects of interleukin-6 (IL-6) and generalized inflammatory factors in this context were quantified as 15.96% (95% CI: 0.0288–0.1971) and 14.25% (95% CI: 0.0167–0.1899), respectively. In addition, another study has shown that dibutyl phthalate (DBP) can induce apoptosis in grass carp hepatocytes, mediated through mechanisms of inflammatory response and oxidative stress [14]. This highlights the broader biological impact of phthalates. In the field of periodontal health, the inflammatory response is intricately connected to the pathogenesis of periodontitis [15]. Maintaining a balance between the body’s defense system and oxidative stress is crucial in preserving periodontal tissue health [16]. The interplay of inflammatory reactions and oxidative stress, often resulting in mutual reinforcement, can lead to increased osteoclast activity and subsequent bone loss. This connection underlines the importance of understanding the complex interplay between environmental factors like phthalate exposure, oxidative stress, and inflammatory responses in the pathogenesis of periodontitis.

Phthalate metabolites have been shown to alter the composition of the gut microbiota in mice [37], which also could have implications for human health through the gut-brain axis [38]. Another study has observed variances in the respiratory tract microbiota among individuals exposed to different phthalate concentrations [39]. Although there are no studies directly linking phthalate metabolites to changes in oral microbiota, the well-established connection between the development of periodontitis and alterations in oral microbiota leads us to hypothesize that phthalate metabolites could influence periodontitis by affecting the microbiota.

In summary, phthalate metabolites may influence periodontitis through three main mechanisms: impacting estrogen function and affecting host inflammation as well as the structure of the microbiome. Future clinical prospective studies should investigate the role of individual biological components in periodontal disease. This includes a thorough examination of host immunity, epigenetic changes, and microbiome composition, all of which are critical to health and disease. By incorporating these variables, we can gain a better understanding of how environmental factors like phthalate exposure contribute to or mediate disease processes. This method will allow for a more thorough investigation of the complex interactions between genetic predisposition, microbial ecology, immune responses, and environmental influences in the development of periodontal disease.

However, it's crucial to recognize the limitations of our study. Firstly, due to its cross-sectional design, we cannot infer a causal link between phthalate metabolites and periodontitis. Secondly, despite adjusting for potential confounders based on prior studies and clinical knowledge, there may still be unmeasured or unknown confounding factors. Thirdly, differentiating the impacts of short-term versus long-term exposure to phthalate metabolites on periodontitis is challenging. Fourthly, the classification criteria for periodontitis used in this study do not allow for a diagnosis in patients with only one tooth. Furthermore, third molars were excluded from the periodontal assessments, potentially leading to an underestimation of the periodontitis prevalence. Lastly, the periodontal examination did not include individuals under 30 years old or those residing in institutional settings like nursing homes, hospitals, hospices, or prisons.

Our study has identified a positive association of certain phthalate metabolites with periodontitis. These findings suggest a potential link between environmental exposures and periodontal health. However, conclusive findings regarding causality are not possible due to the nature of our study design. Therefore, future research should focus on tracking the long-term effects of phthalate metabolite exposure on periodontal health through prospective cohort studies. Additionally, advanced technologies including the microbiome, metabolomics, and proteomics analyses can be integrated with in vitro and in vivo experimental methods to elucidate the potential biological mechanisms linking phthalate exposure to periodontal disease. Only through this continued research can we fully understand the implications of phthalate exposure on oral health and potentially inform public health interventions and policy changes.