Exposure to bisphenols and their relation to diabetes mellitus: a systematic review

Data extraction

The literature search was carried out between February and July 2024. Data were obtained through direct consultation and online access to bibliographic databases in the health sciences, specifically MEDLINE (via PubMed) and Web of Science.

Information processing

To organize and improve the interpretation of the results, the articles were categorized based on study variables, including first author, year of publication, quality index, title, study type, objectives, and findings. The multiplatform program MENDELEY (bibliographic reference manager program) was utilized to refine duplicate records across multiple databases. The search terms were defined by consulting the Thesaurus of Health Sciences Descriptors (DeCS), developed by the Latin American and Caribbean Center for Medical Sciences Information (BIREME), and its equivalent, the Medical Subject Headings (MeSH) from the U.S. National Library of Medicine. Based on the analysis of the hierarchical structure of both the Thesaurus and their indexing records, the following search equations were deemed appropriate, following the PIO format.

Final selection of articles

The risk of bias assessment was conducted using the Cochrane risk of bas tool, with assessors blinded to study outcomes^[19]. Articles meeting the following criteria were chosen for review and critical evaluation, which was conducted by three of the authors of this manuscript. Data correction was managed through the use of dual tables, which facilitated the detection of discrepancies and their resolution by reconsulting the original sources. To obtain more specific information in the literature search, the inclusion and exclusion criteria applied were as follows: Inclusion criteria: All articles published in the last 5 years were included to use the most recent and up-to-date information possible. All searches were conducted in both English and Spanish to achieve comprehensive international knowledge for this study. Studies that mention some of the most relevant and significant symptoms of the disease, such as hyperglycemia and insulin resistance, were included. Reviews, systematic reviews, meta-analyses, and various observational studies on the effect of bisphenol exposure, measured in urine and/or serum, were included.

Exclusion criteria

Animal studies, in vitro research, studies with low methodological quality, those with non-representative samples of the human population, and those that do not control for important confounding factors such as diet or comorbidities will be excluded. Studies that do not distinguish between the different types of BPs (BPA and its analogs), those that do not specifically analyze the relationship between BP exposure and diabetes, and those with incomplete or insufficient results to assess this association will also be discarded. These criteria will ensure that only relevant high-caliber research is included.

Ethical considerations

All data were obtained from the articles selected for review. Therefore, in accordance with Law 14/2007 on biomedical research, ethics committee approval was not necessary for the use of secondary data.

Urine analysis

Serum analysis

BPA. Studies examining BPA exposure in serum have provided important findings about its association with diabetes. In the prospective study by Yang et al. (2021) conducted with Chinese pregnant women, they found that serum BPA concentrations were associated with elevated fasting glucose and insulin levels throughout pregnancy, indicating a higher risk of gestational diabetes (GDM)^[24]. Lee et al. (2021), in a cross-sectional study with Korean adults, found that the fourth quartile of BPA urinary concentration was associated with a higher likelihood of DM compared to the first quartile^[25].

Studies in children

Studies in other demographic groups

Other studies have examined the relationship between BPA and diabetes in different demographic groups. Filardi et al. (2020) found that urinary BPA levels during pregnancy were associated with high post-load glucose levels, especially in women with overweight or obesity, suggesting a link to GDM and T2DM^[30]. Song et al. (2019), in a cohort study conducted in China, found that BPA exposure was associated with abnormal fasting glucose in areas with electronic waste recycling, while BPAF was associated with hypoglycemia in those areas^[31]. Wang et al. (2019), in a longitudinal study, found that urinary BPA was significantly associated with fasting hyperglycemia in non-diabetic women, especially those with overweight or obesity^[32]. Rancière et al. (2019), in a case-control study, did not find significant associations between BPA glucuronide (BPA-G) and incident diabetes at the beginning of the study, but positive associations were found in the third year. Stronger associations were found between BPS and diabetes in women, especially those who were obese and over 50 years old at baseline with a family history of diabetes^[33]. Murphy et al. (2019) found that after adjusting for age, urinary BPA concentrations were associated with diabetes in Mexican women^[34]. Duan et al. (2018), in their case-control study, found that concentrations of BPAF, BPS, and BPA were significantly higher in cases of T2DM than in controls, with a high probability of T2DM in the highest quartiles of BPA^[35].

Studies in pregnant women

Dermal exposure studies

Lee et al. (2018), in a study on dermal BPA exposure among Korean cashiers, found that BPA urinary levels were higher after a shift without gloves and showed a significant association with fasting insulin in adjusted models^[38]. Lind et al. (2018), in their review, found a significant relationship between prevalent diabetes and BPA levels, as well as with other EDs^[39].

Introduction to BPs and diabetes

A wide range of BPs, including BPA, BPS, BPF, and BPAF, have been associated with metabolic disorders, including diabetes. The goal of this review is to find out whether these BPs play a role in the epidemiology of DM. The reviewed material lays the groundwork for more detailed studies of the mechanisms whereby BPs may act to alter glucose metabolism, insulin resistance, and diabetes. It is suggested that these BP compounds act as EDs, which explains the relationships; however, this review seeks to explain how BPs affect metabolism more specifically. It is hoped that through high-caliber research, this work will clarify the issues of the effect of BP exposure on DM and point out the gaps in knowledge to be researched. A total of 7 reviews, one meta-analysis, 5 cohort studies, 3 case-control studies, and 4 cross-sectional studies were identified in the reviewed literature.

Association between bisphenol exposure and diabetes

As can be noted, the outcome measures generated appear to be quite heterogeneous. Overall association patterns linking diabetes and exposure to BPs using fasting hyperglycemia, insulin resistance, or increased risk of T2DM or GDM showed positive links in the majority of the studies reviewed (n = 20)^[20-22]. On the contrary, some authors^[27,36] claimed that BPA exposure and diabetes or metabolic outcomes were not significant. Several substantial reports, including those by others^{[29,34,35,37]}, suggest that while a link between bisphenol exposure and diabetes may exist, it appears weak in certain populations and may depend on the methods or biomarkers utilized. These findings are preliminary and modest at best, but they do point toward a possible positive link between the probability of diabetes and exposure to bisphenol, and therefore, more studies should be done to further explain and hopefully settle these associations. This association is biologically plausible, as DM involves disruptions in glucose metabolism and insulin homeostasis, and various studies have confirmed links between bisphenol exposure and metabolic alterations^[40].

Specific population studies and findings

Several studies have reported positive associations between BPA exposure and DM in specific demographic subgroups, such as by age, sex, or other characteristics. For instance, a longitudinal cohort study^[37] found that BPA exposure was associated with increased fasting hyperglycemia before the onset of diabetes and elevated FPG levels in adults, particularly older adults. Interestingly, these associations were only significant in women. This sex-specific finding could reflect biological or hormonal differences in how BPA is metabolized, rather than being solely attributable to the higher proportion of women in the study (1,467 women versus 869 men). The study further noted that the associations were more pronounced among women classified as obese or overweight. In contrast, Rancière et al. (2009) examined a diverse sample with nearly equal numbers of women and men but did not observe any statistically significant interactions between BPs (BPA and BPS) and sex (P > 0.05)^[33]. Thus, the evidence does not conclusively support stronger links between BPs and DM in women compared to men. Moreover, the limited number of recorded events in the study may affect the reliability of these results. Consistent with the findings of Wang et al. (2019), bisphenol exposure was linked to an increased risk of DM in specific subgroups^[32]. Rancière et al. also highlighted that factors such as BMI, age, and family history of diabetes seemed to influence the relationship between BPS exposure and the onset of DM^[33]. Notably, the risk of developing DM was higher among participants who were overweight or obese at the start of the study, those younger than 50 years, or those with a family history of diabetes. However, these interactions were not statistically significant (P > 0.05), so no firm conclusions can be drawn regarding stronger associations in obese or overweight individuals compared to those with normal weight. On the topic of sex differences, conflicting results have been reported. For example, Moon et al. (2022) found significant positive associations between BPA, BPS exposure, and DM, as well as obesity^[21]. However, when analyzing by gender, they discovered that the positive associations between BPA and DM were present only in men. It has been suggested that these potential sex differences might stem from interactions between BPA and endogenous sex hormones, such as through estrogenic and androgenic signaling pathways. Nevertheless, the results remain inconsistent, with some studies indicating stronger associations in women, while others report them only in men. These inconsistencies highlight the need for further research to understand how sex differences influence the harmful effects of BPs, including exploring possible mechanisms related to hormone signaling pathways^[41].

In summary, the variability in results across studies points to the importance of considering demographic characteristics such as sex, age, BMI, and family history when investigating the relationship between BPs and DM. Further research is necessary to clarify these associations and explore the underlying mechanisms, particularly those related to sex hormones.

The role of obesity and genetic factors

Therefore, it is inferred that it is not clear whether there are gender associations, and it is also suggested that age, genetic predisposition, overweight, and obesity are key factors to consider in the incidence of DM. Regarding the latter, in April 2022, a dose-response meta-analysis found robust results confirming that BPA exposure can increase the risk of obesity and overweight epidemics in children and adolescents^[42]. Similarly, Wu et al. (2020), in a systematic review and meta-analysis, found a positive correlation between BPA levels and the risk of obesity^[43]. Precisely, this obesogenic role of BP could have significant implications in the onset of diabetes, as obesity is a risk factor that can lead to T2DM^[44].

Challenges in study design

One of the limitations found in the majority of studies is the method used to measure biomarkers of exposure to BP. Most studies use urinary BP measurements as a method to assess exposure, while others measure BP in serum to quantify exposure. It is important to note that using different exposure markers leads to a limited biological interpretation. It is not known with certainty whether exposure to BPA is detectable in serum concentrations of BPA^[45], as oral exposure leads to rapid metabolism and subsequent elimination in the urine as conjugates, given that BPA is a lipophilic compound and its free form is insoluble in water^[46].

It has been documented that transdermal and sublingual absorption of BPA can occur; thus, in these cases, the compound would not be completely metabolized^[47,48]. However, it appears that free BPA levels are not detectable in the general population through serum measurements. According to Teeguarden et al. (2011), BPA undergoes nearly complete renal elimination, suggesting that urinary BPA measurement is a useful biomarker for assessing human exposure to BPA^[49]. Most studies utilize urinary BPA measurements as a biomarker because they are easy to collect and have a lower risk of contamination. Nine studies found significant links between urinary BPA levels and metabolic risks, including hyperglycemia, obesity, insulin resistance, T2DM, or GDM^{[20-23,30,32,34,35,38]}, while two studies did not find any significant relationships^[27,29]. In terms of serum BPA, two studies reported positive associations with insulin resistance and fasting glucose^[24,38], while one study did not find consistent connections^[31].

Limitations of study designs and sample sizes

One significant limitation found in the majority of studies is the lack of consideration for the time of day and the frequency of sample collection, which can lead to erroneous classification of BPA exposure levels, thus attenuating the association between BPA and the findings obtained. During the 9-year duration of the case-control study by Ranciére et al. (2019), urine and blood samples were collected only at 4 time points, corresponding to visits at baseline, the third year, sixth year, and ninth year, showing an association between BPA and BPS and incident DM at the 3-year mark^[32]. However, this collection method may not accurately represent long-term exposure to these BPAs. Ye et al. (2011) collected 427 urine samples over 7 consecutive days from 8 individuals, considering factors such as food intake, beverages, and medications, among others, and observed significant interindividual and intraindividual variability in urinary BPA concentrations, both in samples collected on a single day and those collected over 7 days^[50]. Therefore, due to the variability in absorption, metabolism, and elimination in individual participants, urinary concentrations of BPA can significantly fluctuate throughout the day. Hence, it is recommended to record the time of sample collection in biomonitoring studies and to consider other confounding factors such as previous dietary intake, the time of sample collection relative to meals, and the elapsed time since food consumption, among others^[50,51].

Small sample sizes and limited generalizability

Several studies are limited by small sample sizes, which can lead to findings that are not representative of the general population. For example, in the study by Song et al. (2019), only 119 subjects living in villages near electronic waste recycling areas were included, of whom only 46 were males^[31]. This study indicated a link between elevated BPA concentrations and abnormal fasting glucose levels, compared to only 6 male subjects from control areas distant from recycling sites. The small number of participants in the control group undermines the reliability and representativeness of the results. Similarly, Kataria et al. (2017) did not find associations between urinary BP concentrations and insulin resistance in 41 healthy children from the New York area, which contradicted expected outcomes, possibly due to the limited sample size as explained by the authors^[29]. In contrast, Moon et al. (2022) demonstrated a link between BPA and BPS with diabetes and obesity in a large, representative sample of 3,780 adult Korean participants, where the gender proportion was equitable^[21].

Specific population groups and limitations

There are also studies that have focused solely on specific population groups. For instance, Murphy et al. (2019) in a case-control study linked urinary BPA levels to a higher risk of DM in a group of Mexican women, making these findings not generalizable to the broader population^[34]. This study also highlights a significant limitation regarding the method of DM diagnosis, as it relied on self-reported information from participants without initial diagnostic testing to confirm the presence of diabetes. While this approach reduces costs, participants may have made dietary or lifestyle changes after being diagnosed with DM, potentially influencing BPA exposure and introducing errors in associations^[33]. Additionally, there’s a possibility that undiagnosed diabetic individuals were inadvertently included in the control group, leading to partially biased associations. This was noted by Jung et al., who found that 35% of subjects were unaware of their diabetic status from 2016 to 2018^[52].

Diverse study designs and findings

In a longitudinal study published by Wang et al. (2019), they explored the relationship between BPA exposure and disruptions in glucose homeostasis among 2,356 non-diabetic individuals^[32]. By selecting a sample of healthy participants, potential biases related to lifestyle changes and treatment after diabetes diagnosis were indirectly mitigated. Moreover, this study provided new insights into BPA’s impact on glucose homeostasis even within normal blood glucose ranges. Therefore, it is recommended to use diagnostic tests for DM to confirm diagnoses more reliably and avoid potential errors in study outcomes^[31].

It appears that the studies reviewed encompass a variety of designs and age groups, providing a comprehensive look into the association between BPA and DM. Specifically, Rotondo et al. (2020) linked BPA exposure in healthy children to prevalent DM and insulin resistance^[28]. Similarly, Predieri et al. (2020) found that children with type 1 diabetes mellitus (T1DM) exhibited higher concentrations of BPA compared to healthy children^[26]. The review also includes other study designs, such as cross-sectional or prevalence studies, as well as observational studies like case-control studies - for example, Duan et al. (2018) demonstrated higher concentrations of total BP, BPS, and BPAF in cases compared to controls^[35]. Furthermore, prospective studies, such as Zhang et al.’s (2019), found that BPS and BPAF were associated with increased fasting glucose levels in pregnant women, although statistically significant associations with GDM were not found for BPA, BPS, and BPF^[36]. However, Yang et al. (2021) reported that serum BPA was associated with higher levels of fasting glucose, insulin, and HOMA-IR in pregnant women. These studies collectively highlight various aspects of BPA exposure and its potential links to different forms of diabetes across diverse populations and age groups, contributing to a broader understanding of the association between BPA exposure and DM^[24].

Research gaps and the need for prospective studies

The research on BPs, particularly BPA, and their potential association with DM suggests significant hypotheses, yet does not establish causality due to the observational nature of most studies. The lack of prospective research linking BPs with DM limits definitive cause-and-effect conclusions. Prospective studies with large, diverse populations and extended durations are needed but face logistical challenges and costs. Intervention studies in humans are impractical and unethical, emphasizing reliance on observational data. Additionally, chronic exposure to a variety of EDs, including BPA and its analogs like BPS, BPF, and BPAF, may lead to cumulative effects beyond individual substance thresholds. Current regulatory frameworks often focus on BPA alone, neglecting other potentially harmful BPs. Establishing realistic and safe acceptable daily intakes (ADIs) for BPA and its analogs is crucial, considering both individual and combined effects in future research. Scientific evidence supports an association between BPA exposure and DM, with emerging links to other BPs, albeit requiring further robust study designs. Environmental factors, including ED exposure, are increasingly recognized as significant contributors to diabetes incidence, mortality, and associated costs. Addressing these factors collectively can potentially mitigate the diabetes epidemic and redirect resources toward societal needs. In conclusion, ongoing research should aim to clarify the relationships between BPs and chronic metabolic diseases like DM. This endeavor holds promise for reducing disease burden, improving quality of life, and optimizing resource allocation for broader societal benefit.

Strengths of the study

Comprehensive Review: The study conducts an exhaustive review that includes various study designs and age groups, providing a broad perspective on the association between BPs, especially BPA, and DM. Inclusion of Diverse Study Types: The review encompasses reviews, meta-analyses, cohort studies, case-control studies, and cross-sectional studies, enriching the understanding of how BPA exposure relates to different forms of diabetes in diverse populations. Studies in Young Populations: Specific studies highlighting associations between BPA exposure and DM in children, such as those by Rotondo et al. (2020) and Predieri et al. (2020), are emphasized, providing valuable insights into the effects of early BPA exposure^[26,28].

Limitations of the study

Observational Nature of Studies: Most reviewed studies are observational, preventing the definitive establishment of causality between BP exposure and DM. The lack of prospective studies limits the ability to draw firm conclusions about cause-and-effect relationships. Limitations in Biomarker Measurement: There is variability in the methods used to measure BP exposure biomarkers across studies. Some use BPA measurements in urine while others use serum, which may introduce biases in exposure assessment and complicate direct comparisons between studies. Small Sample Sizes in Some Studies: The inclusion of small samples in certain studies limits the generalizability of findings to broader populations. This is evident in studies focused on specific demographic groups, such as the study by Murphy et al. (2019) on Mexican women, which may not adequately represent the general population’s susceptibility to health impacts related to BPA. In addition, despite considering the possibility of conducting a meta-analysis, it was decided that a meta-analysis may not be necessary due to the diversity of the studies and their varied methodologies and objectives^[34].

Conclusion

Exposure to various BPs, such as BPA, BPS, BPF, and BPAF, has been associated with metabolic disorders, including DM. The results of most of the studies reviewed suggest a positive relationship between exposure to these compounds and an increased risk of diabetes, although some associations are weak or inconsistent.

While some studies have reported stronger associations in women, others indicate that these links could depend on factors such as overweight, obesity, age, and genetic predisposition. However, it has not been conclusively confirmed whether sex significantly influences the relationship between BPs and diabetes.

Obesity is identified as an important factor that could amplify the adverse effects of bisphenol exposure on diabetes, as several studies suggest that obesity may increase the risk of T2DM associated with these compounds.

Current findings are preliminary, so further research with prospective designs, larger samples, and standardized methodologies is needed to better understand how BPs affect metabolism and diabetes. It is also important to investigate the interaction of BPs with other endocrine factors, such as sex hormones.

Urinary BPA biomarkers are generally more useful for assessing exposure as they allow for sample collection with a lower risk of contamination compared to serum measurements. However, interindividual and intraindividual variability in urinary BPA levels must be considered when interpreting the results.

Since exposure to BPs is associated with a higher incidence of diabetes and other metabolic disorders, it is essential for public policies to consider stricter regulation of products containing BPs and explore safer alternatives to reduce human exposure to these compounds.

In summary, while there are links between BPs and diabetes, the findings are inconsistent, and further research is required to fully understand the mechanisms involved and their implications for public health.