The Mediating Role of Oxidative Stress in the Association Between Phthalate Exposure and Body Mass Index Among Adults: A Cross-Sectional Analysis Using NHANES Data

doi:10.21203/rs.3.rs-5127539/v1

Download PDF

Research Article

The Mediating Role of Oxidative Stress in the Association Between Phthalate Exposure and Body Mass Index Among Adults: A Cross-Sectional Analysis Using NHANES Data

https://doi.org/10.21203/rs.3.rs-5127539/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

The study investigates the mediating role of oxidative stress in the relationship between phthalate exposure, measured via urinary Bisphenol A (BPA) levels, and Body Mass Index (BMI) in adults. Given the global prevalence of obesity and the widespread exposure to phthalates, understanding this relationship is critical. Methods: Data were derived from the National Health and Nutrition Examination Survey (NHANES), focusing on adult participants. Key variables included urinary BPA levels (independent variable), BMI (dependent variable), oxidative stress indicators (mediator), and covariates such as age, serum creatinine, poverty index, and race/ethnicity. Descriptive statistics summarized baseline characteristics, and mediation analysis quantified the direct, indirect, and total effects of phthalate exposure on BMI. Results: The study sample comprised 19,022 adults, with a nearly equal distribution of males and females. The median BMI and urinary BPA levels differed significantly by gender. Mediation analysis revealed that oxidative stress mediated approximately 19% of the total effect of phthalate exposure on BMI. The Average Causal Mediation Effect (ACME) was − 0.000976 (95% CI: -0.001147 to 0.001, p < 0.001), and the Average Direct Effect (ADE) was − 0.004155 (95% CI: -0.008239 to 0.001, p = 0.016). The total effect was − 0.005132 (95% CI: -0.008997 to 0.001, p = 0.004). Conclusions: This study highlights the significant role of oxidative stress in mediating the relationship between phthalate exposure and BMI. The findings suggest that strategies to reduce oxidative stress could mitigate the obesogenic effects of phthalates, underscoring the need for regulatory policies to limit phthalate exposure and public health interventions targeting oxidative stress. Future research should explore longitudinal data and a broader range of phthalate exposures to further elucidate these relationships.

Phthalate exposure

Oxidative stress

Body Mass Index

The increasing prevalence of obesity has become a significant public health concern globally, necessitating comprehensive research into its underlying causes and contributory factors (Boutari C et al., 2022). One area of growing interest is the potential role of environmental pollutants, such as phthalates, in influencing body weight and metabolism. Phthalates are a group of chemicals commonly used as plasticizers in flexible plastic production and as ingredients in personal care products (Wormuth et al., 2006). Their widespread use has led to ubiquitous human exposure, primarily through ingestion, inhalation, and dermal absorption (Latini et al., 2017).

Recent studies have suggested that phthalate exposure may be linked to various adverse health outcomes, including obesity (Hatch et al., 2008). Phthalates can disrupt endocrine function, leading to alterations in metabolic processes and potentially contributing to weight gain (Meeker et al., 2009). Oxidative stress, a condition characterized by an imbalance between the production of reactive oxygen species and the body’s ability to detoxify these reactive intermediates, has been proposed as a key mediator in the relationship between phthalate exposure and obesity (James et al., 2015).

Oxidative stress can damage cellular components, impair metabolic functions, and trigger inflammatory responses, all of which are implicated in the development of obesity and related metabolic disorders (Roberts et al., 2013). Therefore, understanding the mediating role of oxidative stress in the association between phthalate exposure and body mass index (BMI) is crucial for elucidating the mechanisms underlying this relationship.

This study aims to investigate the mediating role of oxidative stress in the association between phthalate exposure and BMI among adults using data from the NHANES. By leveraging a cross-sectional dataset, this analysis seeks to provide insights into how environmental exposures impact metabolic health and may inform future public health interventions aimed at reducing obesity prevalence and associated comorbidities.

2.1. Data Source:

The data for this analysis was obtained from the NHANES from 2009–2010. NHANES is a cross-sectional survey designed to evaluate the health and nutritional status of both adults and children in the United States. It involves a combination of interviews, physical examinations, and laboratory tests. Based on the available data, we selected the 2009–2010 survey cycle.

2.2. Study Population

The study focused on adult participants from NHANES. Key criteria for inclusion involved the availability of relevant biomarkers, such as urinary Bisphenol A (BPA) levels, serum creatinine, and other health indicators. The characteristics of the study population were stratified by gender, providing a comparative analysis between male and female participants.

2.3. Exposure and Outcome Variables

The analysis included several key variables. The independent variable was phthalate exposure, measured through urinary Bisphenol A (BPA) levels. The dependent variable was Body Mass Index (BMI). Oxidative stress indicators served as the mediator variable. Covariates included age, serum creatinine, poverty index, and race/ethnicity, which were used to control for potential confounding factors.

2.4. Statistical Analysis

Descriptive statistics were first calculated to describe the baseline characteristics of the study participants. For continuous variables, the median and interquartile range (IQR) were provided, while categorical variables were presented as frequencies and percentages. A mediation analysis using survey design was conducted to explore the role of oxidative stress in the relationship between phthalate exposure and BMI. Specifically, the analysis estimated the Average Causal Mediation Effect (ACME), representing the indirect effect mediated by oxidative stress. The Average Direct Effect (ADE), representing the direct effect of phthalate exposure on BMI, not mediated by oxidative stress, was also assessed. The total effect, incorporating both direct and mediated effects, was measured. Additionally, the proportion of the total effect that was mediated by oxidative stress was calculated. R, a statistical software, was used for the analysis, employing specific packages for statistical and mediation analysis. Results were presented with Bootstrap styling for better visualization and interpretation.

3.1. Baseline Characteristics

The study sample consisted of 19,022 adults, with 9,571 males and 9,451 females. Table 1 presents the baseline characteristics of the participants stratified by gender. The median age was slightly higher in males (47 years, IQR: 32–62) compared to females (45 years, IQR: 30–62). Both genders had similar median BMI values, with males showing a BMI of 28 (IQR: 25–32) and females reporting a BMI of 28 (IQR: 24–33). The levels of urinary Bisphenol A (BPA) varied significantly between genders, with males having lower median levels (9 ng/mL, IQR: 3–36) compared to females (20 ng/mL, IQR: 5-133). Serum creatinine levels also differed, with males presenting higher values (0.95 mg/dL, IQR: 0.86–1.08) than females (0.74 mg/dL, IQR: 0.64–0.84). The poverty index showed some variation, with males having a slightly higher median value (2.06, IQR: 1.11–4.12) than females (1.71, IQR: 0.91–3.59). The racial distribution was fairly consistent across both genders, with the majority being Non-Hispanic White (47% males and 50% females), followed by Non-Hispanic Black and Mexican American.

Table 1

Baseline Characteristics of Study Participants by Gender
Characteristic	Male, N = 957¹	Female, N = 945¹
Age in Year	47 (32, 62)	45 (30, 62)
Body Mass Index	28 (25, 32)	28 (24, 33)
Urinary Bisphenol A	9 (3, 36)	20 (5, 133)
Serum Creatinine	0.95 (0.86, 1.08)	0.74 (0.64, 0.84)
Poverty Index	2.06 (1.11, 4.12)	1.71 (0.91, 3.59)
Races
Mexican American	195 (20%)	156 (17%)
Other Hispanic	87 (9.1%)	105 (11%)
Non-Hispanic White	453 (47%)	477 (50%)
Non-Hispanic Black	163 (17%)	156 (17%)
Other Race - Including Multi-Racial	59 (6.2%)	51 (5.4%)
¹ Median (IQR); n (%)

Table 2

Summary of Mediation Analysis Results
Measure	Estimate	95% CI Lower	95% CI Upper	p-value
ACME	-0.000976	-0.001147	0.001	< 0.001
ADE	-0.004155	-0.008239	0.001	0.016
Total Effect	-0.005132	-0.008997	0.001	0.004
Prop. Mediated	0.190250	0.043939	0.46	0.004

3.2. Mediation Analysis

The mediation analysis results explored the role of oxidative stress as a mediator in the association between phthalate exposure and BMI. The Average Causal Mediation Effect (ACME) was estimated at -0.000976, with a 95% confidence interval ranging from − 0.001147 to 0.00 and a highly significant p-value of less than 0.001. The Average Direct Effect (ADE) was found to be -0.004155 (95% CI: -0.008239 to 0.001, p = 0.016), indicating a significant direct impact of phthalate exposure on BMI. The total effect, which combines both direct and mediated effects, was − 0.005132 (95% CI: -0.008997 to 0.001, p = 0.004). Notably, the proportion of the total effect mediated by oxidative stress was 0.190250, with a 95% confidence interval of 0.043939 to 0.46 and a p-value of 0.004, indicating that approximately 19% of the effect of phthalate exposure on BMI is mediated through oxidative stress. These results underscore the significant role that oxidative stress plays in the linkage between phthalate exposure and BMI, indicating potential pathways for intervention and further research.

The present study elucidates the intricate relationship between phthalate exposure, oxidative stress, and BMI among adults, utilizing data from the NHANES. The mediation analysis provided compelling evidence that oxidative stress significantly mediates the relationship between exposure to phthalates, as indicated by BPA, and increased BMI. This discussion explores the implications of these findings in light of existing literature and potential mechanisms.

The association between phthalate exposure and obesity has been well-documented in epidemiological studies (Wu, Q et al., 2023; Kim, S. H. et al., 2014; Dubey P et al., 2022). Phthalates, widely used as plasticizers, are prevalent in various consumer products, leading to widespread human exposure (Singh & Li, 2011). Previous research has demonstrated that phthalates can act as endocrine disruptors, interfering with lipid and glucose metabolism, which can contribute to obesity (Hatch et al., 2010). Our study corroborates these findings, showing that higher urinary BPA levels are associated with an increase in BMI.

Oxidative stress emerges as a critical mediator in the pathway linking phthalate exposure to obesity (Ferguson, K. K. et al., 2017; Tanner, S.et al., 2022). Reactive oxygen species generated during oxidative stress can damage cellular lipids, proteins, and DNA, impairing cellular function and contributing to chronic metabolic disorders such as obesity and diabetes (Roberts & Sindhu, 2013). Our analysis revealed that oxidative stress mediates approximately 19% of the total effect of phthalate exposure on BMI. This finding is consistent with experimental studies suggesting that phthalates induce oxidative stress, which in turn disrupts metabolic homeostasis (James et al., 2015).

The mechanistic underpinnings of how oxidative stress mediates the relationship between phthalate exposure and obesity are multifaceted. Phthalates can activate peroxisome proliferator-activated receptors (PPARs), which regulate gene expression involved in adipogenesis and lipid metabolism (Feige et al., 2007). Moreover, oxidative stress can exacerbate inflammation, further promoting adipocyte dysfunction and insulin resistance, key features of obesity (Xu et al., 2003). The mediation analysis underscores the importance of oxidative stress in this pathway, suggesting that interventions aimed at reducing oxidative stress might mitigate the obesogenic effects of phthalate exposure.

The findings of this study have significant public health implications. Given the ubiquitous nature of phthalate exposure and the burgeoning obesity epidemic, understanding the mediating role of oxidative stress offers potential avenues for intervention. Strategies to minimize phthalate exposure, such as regulatory policies limiting the use of phthalates in consumer products, coupled with lifestyle interventions targeting oxidative stress (e.g., antioxidant-rich diets, physical exercise), could be effective in curbing obesity rates (Holtcamp, 2012). Furthermore, these findings warrant the inclusion of oxidative stress biomarkers in future epidemiological studies to better understand environmental determinants of obesity.

While this study provides valuable insights, several limitations must be acknowledged. The cross-sectional nature of NHANES data precludes causal inferences. Longitudinal studies are necessary to establish temporal relationships and causality. Additionally, while urinary BPA was used as a biomarker for phthalate exposure, BPA represents only one of many phthalates, and a more comprehensive assessment might provide a broader understanding of phthalate exposure. Future research should also explore genetic and epigenetic factors that might modulate individual susceptibility to phthalate-induced oxidative stress and obesity.

Our study highlights the mediating role of oxidative stress in the association between phthalate exposure and BMI, emphasizing the need for integrated strategies to address this public health concern. Continued research into the mechanisms and broader environmental exposures will be critical in developing effective interventions to mitigate the adverse health impacts of phthalates.

Ethics approval and consent to participate: Ethics approved by NHANES - NCHS Research Ethics Review Board.

Consent for publication: No

Availability of data and material: All relevant data are within the manuscript, and available on

https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?BeginYear=2009

Competing interests: No

Funding: There has been no significant financial support for this work that could have influenced its outcome.

Author contribution statement: RKR: Conceived and designed the experiments, wrote the paper, Performed the experiments, analyzed and interpreted the data, contributed reagents, materials, analysis tools or data.

Acknowledgements: None

Wormuth M, Scheringer M, Vollenweider M, Hungerbuhler K. What are the sources of exposure to eight frequently used phthalic acid esters in Europeans? Risk Anal. 2006;26(3):803–24.
Latini G, Verrotti A, Felice DE, C. Di-2-ethylhexyl phthalate and endocrine disruption: A review. Curr Drug Targets-Immune Endocr Metabolic Disorders. 2017;4(1):37–40.
Hatch EE, Nelson JW, Stahlhut RW, Webster TF. Association of endocrine disruptors and obesity: perspectives from epidemiological studies. Int J Androl. 2008;31(2):278–84.
Meeker JD, Sathyanarayana S, Swan SH. Phthalates and other additives in plastics: human exposure and associated health outcomes. Philosophical Trans Royal Soc B. 2009;364(1526):2097–113.
James TV, Meeker JD, White KR, Park SK. Urinary phthalate metabolite concentrations and oxidative stress and inflammation in pregnant women: A repeated measures analysis. Environ Health Perspect. 2015;123(3):210–6.
Roberts CK, Sindhu KK. Oxidative stress and metabolic syndrome. Life Sci. 2013;84(21–22):705–12.
Singh S, Li SS. Epigenetic effects of environmental chemicals bisphenol A and phthalates. Int J Mol Sci. 2011;12(5):2410–37.
Feige JN, Gerber A, Casals-Casas C, Yang Q, Winkler C, Bedu E, Wahli W. The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific PPARα-dependent mechanisms. Environ Health Perspect. 2007;115(8):1159–65.
Hatch EE, Nelson JW, Qureshi MM, Weinberg J, Moore LL, Singer M, Webster TF. Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999–2002. Environ Health. 2010;9:21.
Holtcamp W. Obesogens: an environmental link to obesity. Environ Health Perspect. 2012;120(2):a62–8.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig. 2003;112(12):1821–30.
Boutari C, Mantzoros CS. A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on. Metab Clin Exp. 2022;133:155217. https://doi.org/10.1016/j.metabol.2022.155217.
Wu Q, Li G, Zhao CY, Na XL, Zhang YB. Association between phthalate exposure and obesity risk: A meta-analysis of observational studies. Environ Toxicol Pharmacol. 2023;102:104240. https://doi.org/10.1016/j.etap.2023.104240.
Kim SH, Park MJ. Phthalate exposure and childhood obesity. Annals Pediatr Endocrinol metabolism. 2014;19(2):69–75. https://doi.org/10.6065/apem.2014.19.2.69.
Dubey P, Reddy SY, Singh V, et al. Association of Exposure to Phthalate Metabolites With Sex Hormones, Obesity, and Metabolic Syndrome in US Women. JAMA Netw Open. 2022;5(9):e2233088. 10.1001/jamanetworkopen.2022.33088.
Ferguson KK, Chen YH, VanderWeele TJ, McElrath TF, Meeker JD, Mukherjee B. Mediation of the Relationship between Maternal Phthalate Exposure and Preterm Birth by Oxidative Stress with Repeated Measurements across Pregnancy. Environ Health Perspect. 2017;125(3):488–94. https://doi.org/10.1289/EHP282.
Tanner S, Thomson S, Drummond K, O'Hely M, Symeonides C, Mansell T, Saffery R, Sly PD, Collier F, Burgner D, Sugeng EJ, Dwyer T, Vuillermin P, Ponsonby AL, On Behalf Of The Barwon Infant Study Investigator Group. A Pathway-Based Genetic Score for Oxidative Stress: An Indicator of Host Vulnerability to Phthalate-Associated Adverse Neurodevelopment. Antioxid (Basel Switzerland). 2022;11(4):659. https://doi.org/10.3390/antiox11040659.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

The Mediating Role of Oxidative Stress in the Association Between Phthalate Exposure and Body Mass Index Among Adults: A Cross-Sectional Analysis Using NHANES Data

Status:

Version 1

Abstract

Background

1. Introduction

2. Methodology

2.1. Data Source:

2.2. Study Population

2.3. Exposure and Outcome Variables

2.4. Statistical Analysis

3. Results

3.1. Baseline Characteristics

3.2. Mediation Analysis

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

Status:

Version 1