Investigating the Mediating Effects of Urinary Phenols and Parabens on the Relationship Between Phthalate Exposure and Metabolic Changes in Adults

doi:10.21203/rs.3.rs-5149501/v1

Background

Phthalates and other environmental contaminants, such as phenols and parabens, have been implicated in metabolic health disturbances. This study investigates the mediating effects of urinary phenols and parabens on the relationship between phthalate exposure and Metabolic Changes in adults. Methods: Data from the National Health and Nutrition Examination Survey (NHANES) 2009–2010 cycle were utilized, encompassing 1,669 adults. Phthalate exposure was measured via urinary Ethyl Paraben. BMI served as a proxy for metabolic health changes. The analysis employed mediation models to explore whether urinary phenols and parabens mediate the relationship between phthalate exposure and metabolic Changes, adjusting for covariates. Results: The median age of participants was 46 years, with nearly equal gender distribution (51% males and 49% females). The mediation analysis revealed significant mediation effects for Benzophenone-3 and Propyl Paraben. For Benzophenone-3, the Average Causal Mediation Effect (ACME) was − 0.000773 (95% CI: -0.001242 to 0.000, p < 2e-16), and the direct effect (ADE) was − 0.004198 (95% CI: -0.008295 to 0.000, p = 0.016). Similarly, Propyl Paraben presented significant mediation with an ACME of -0.00105 (95% CI: -0.00159 to 0.000, p = 0.020), and the direct effect (ADE) was − 0.00393 (95% CI: -0.00789 to 0.000, p = 0.036). Conclusion: This study provides robust evidence that specific urinary phenols and parabens significantly mediate the relationship between phthalate exposure and metabolic Changes, shedding light on the pathways through which environmental contaminants might influence metabolic health. The findings underscore the necessity for further research and regulatory measures to mitigate exposure to these chemicals and their impacts on metabolic health.

Phthalates

Benzophenone-3

Propyl Paraben

Metabolic Health

Metabolic health is a multifaceted concept influenced by various environmental and genetic factors. Phthalates, a class of endocrine-disrupting chemicals widely used in plastics and consumer products, are pervasive environmental contaminants. These compounds can leach into food and water, leading to widespread human exposure (Smith et al., 2015). Of particular concern is the potential impact of phthalates on metabolic health, as evidenced by several epidemiological studies linking phthalate exposure to adverse metabolic outcomes such as obesity, insulin resistance, and cardiovascular diseases (Kim et al., 2019; Wang et al., 2020).

Body Mass Index (BMI) is a widely used measure in epidemiological studies to assess body fatness and related health risks (WHO, 2000). While BMI has limitations, it remains a valuable proxy for metabolic health changes in large population studies. Elevated BMI is associated with an increased risk of metabolic syndrome, type 2 diabetes, and other metabolic disorders (Ng et al., 2014).

Emerging evidence suggests that other environmental chemicals, such as urinary phenols and parabens, might also interact with metabolic processes. Phenols and parabens are used as preservatives in cosmetics, pharmaceuticals, and food products. These compounds have been detected in human urine, indicating widespread exposure (Calafat et al., 2008). The role of these chemicals as potential mediators in the relationship between phthalate exposure and metabolic changes is not well understood. However, some studies suggest that they might contribute to metabolic alterations through disruption of endocrine function and inflammatory pathways (Kasco et al., 2017; Matsumoto et al., 2021).

Given the ubiquitous nature of these environmental contaminants, understanding their combined effects on metabolic health is crucial. This study aims to investigate the mediating effects of urinary phenols and parabens on the relationship between phthalate exposure and metabolic changes in adults, using BMI as an indicator of metabolic health. By employing a mediation analysis approach, we seek to elucidate the pathways through which phthalate exposure might influence metabolic outcomes.

2.1. Study Sample

This cross-sectional study utilized data from the NHANES 2009–2010 cycle. The study sample comprised adults aged 18 years and older who had complete data for the variables of interest. Data were extracted from NHANES datasets, including Environmental Phenols, Body Measurements, Biochemistry Profile, Demographic Data, and Volatile Organic Compounds. The merged dataset ensured alignment using the unique participant identifier, and only those with complete case data were included to maintain the integrity of the analysis.

2.2. Study Design

The study design accounted for NHANES's complex survey methodology, which employs a multistage probability sampling design. Essential design variables included the primary sampling unit, strata, and sampling weights. These elements were incorporated to accurately reflect the survey's sampling strategy and allow for generalization to the US population.

2.3. Exposure, Outcome, and Mediators

The primary exposure variable in this study was phthalate exposure, measured by the urinary concentration of ethyl paraben. The outcome variable was Body Mass Index, a widely used indicator of metabolic health. This study focused on six urinary phenols and parabens as potential mediators: benzophenone-3, butyl paraben, methyl paraben, ethyl paraben, triclosan, and propyl paraben. To control potential confounding factors, several covariates were included in the models: Age, Gender, Race/Ethnicity, Income-to-Poverty Ratio.

2.4. Statistical Analysis

The analysis included two primary models: a mediator model and an outcome model. The mediator model assessed the association between phthalate exposure and each mediator (urinary phenols and parabens), adjusting for age, gender, race/ethnicity, and income-to-poverty ratio. The outcome model evaluated the relationship between phthalate exposure, each mediator, and Body Mass Index, adjusted for the same covariates. Mediation analysis was conducted using the mediate function from the mediation package in R. This analysis estimated the Average Causal Mediation Effect (ACME), Average Direct Effect (ADE), Total Effect, and Proportion Mediated. To determine the significance of the mediation effects, bootstrapping with 500 simulations was implemented to generate confidence intervals and p-values. Mediation effects were considered significant if the p-values for ACME (d0.p or d1.p) were below the threshold of 0.05.

3.1. Descriptive Result

The study examined a sample of 1,669 adults from the NHANES 2009–2010 cycle. The median age of participants was 46 years, with an interquartile range (IQR) of 31 to 61 years, indicating a diverse age distribution. Gender representation was nearly equal, comprising 51% males and 49% females. The sample included a significant proportion of Non-Hispanic White individuals (51%), along with considerable representation from Mexican American (17%), Non-Hispanic Black (17%), Other Hispanic (9.1%), and individuals identifying as Other Race, including multi-racial (5.9%). The median income-to-poverty ratio was 1.85, suggesting a varied socioeconomic status among the participants. Urinary concentrations of different phenols and parabens revealed considerable variability. For instance, Benzophenone-3, Butyl Paraben, Methyl Paraben, Ethyl Paraben, Triclosan, and Propyl Paraben exhibited wide ranges, reflecting diverse exposure levels among the participants. The median Body Mass Index (BMI) was 28, indicative of an overweight population, and the median waist circumference was 97 cm, reinforcing concerns of central obesity.

3.2. Mediation Analysis:

The mediation analysis identified significant mediation effects of Benzophenone-3 and Propyl Paraben on the relationship between phthalate exposure (measured via urinary Ethyl Paraben) and metabolic Changes. Specifically, Benzophenone-3 showed that part of the relationship between phthalate exposure and metabolic Changes was mediated through this chemical, suggesting that higher levels of Benzophenone-3 are associated with changes in metabolic. This mediation effect was significant, with an Average Causal Mediation Effect (ACME) of -0.000773 (95% CI: -0.001242 to 0.00, p < 0.0001). The direct effect (ADE) of phthalate exposure on metabolic Changes was − 0.004198 (95% CI: -0.008295 to 0.00, p = 0.016), and the total effect was − 0.004971 (95% CI: -0.008995 to 0.00, p = 0.008). The proportion of the effect mediated was 0.155445 (95% CI: 0.039286 to 0.44, p = 0.008), indicating that the presence of Benzophenone-3 could partially explain how phthalate exposure contributes to increased metabolic Changes. Similarly, Propyl Paraben was found to mediate this relationship significantly, with an ACME of -0.00105 (95% CI: -0.00159 to 0.00, p = 0.020). The direct effect (ADE) of phthalate exposure on metabolic Changes was − 0.00393 (95% CI: -0.00789 to 0.00, p = 0.036), and the total effect was − 0.00497 (95% CI: -0.00898 to 0.00, p = 0.008). The proportion of the effect mediated by Propyl Paraben was 0.21038 (95% CI: 0.01928 to 0.76, p = 0.028).

This study illuminates the significant mediating effects of specific urinary phenols and parabens on the relationship between phthalate exposure and metabolic change in adults. Benzophenone-3 and Propyl Paraben were found to mediate the effect of phthalate exposure on BMI, underscoring the complex interplay between environmental contaminants and metabolic health outcomes.

Phthalates are established endocrine-disrupting chemicals associated with metabolic disturbances, including obesity and insulin resistance (Genuis et al., 2012). Previous research has demonstrated that phthalates interfere with hormonal regulation and energy homeostasis, which can contribute to metabolic diseases (Hatch et al., 2008). This study corroborates these findings by showing that phthalate exposure, measured via urinary Ethyl Paraben, is linked to increased metabolic change. Importantly, our mediation analysis revealed that a substantial portion of this relationship is mediated by Benzophenone-3 and Propyl Paraben.

Benzophenone-3, commonly used in sunscreens and personal care products, has been shown to disrupt endocrine functioning (Gonzalez et al., 2007). The mediation effect of Benzophenone-3, reflected by an Average Causal Mediation Effect (ACME) of -0.000773, indicates that higher urinary levels of Benzophenone-3 are significantly associated with changes in metabolic change. The direct effect (ADE) reduced to -0.004198 when accounting for Benzophenone-3 suggests that this chemical partially mediates the relationship between phthalate exposure and metabolic Changes. This supports the hypothesis that Benzophenone-3's endocrine-disruptive properties lead to metabolic changes, potentially through mechanisms involving hormonal imbalance and lipid metabolism interference (Schmutzler et al., 2004; Janjua et al., 2008).

Similarly, Propyl Paraben, widely used as a preservative in cosmetics and pharmaceuticals, showed a significant mediation effect with an ACME of -0.00105. The direct effect (ADE) of phthalate exposure on metabolic change was − 0.00393, and the total effect was − 0.00497. This mediation indicates that Propyl Paraben also substantially affects the relationship between phthalate exposure and metabolic Changes. Propyl Paraben's ability to mimic estrogen and disrupt endocrine function is documented, contributing to weight gain and increased BMI (Darbre & Harvey, 2008; Vo et al., 2010). The proportion mediated, 0.21038, emphasizes the significant role of Propyl Paraben in this pathway.

The robustness of these findings, confirmed through bootstrapping with 500 simulations, underscores the validity of the observed mediation effects. These results highlight the necessity of considering multiple environmental chemicals to understand the scope of metabolic disruption due to phthalate exposure. The mechanisms by which these mediators influence BMI are likely multifaceted. For example, Benzophenone-3 and Propyl Paraben may disrupt hormonal pathways critical for metabolism, including thyroid hormone regulation and the impact on adipogenesis (Boas et al., 2006). Additionally, these chemicals might contribute to oxidative stress and systemic inflammation, further exacerbating metabolic disorders (Balakrishnan et al., 2017; Saygili et al., 2015). The findings hold significant public health implications. Given the widespread human exposure to phthalates, Benzophenone-3, and Propyl Paraben, regulatory measures to limit exposure are vital to mitigate adverse health effects. Public health interventions should aim at reducing the use of products containing these compounds, especially among vulnerable groups such as children and pregnant women.

Future research should focus on elucidating the underlying biological mechanisms by which these mediators affect metabolic change. Longitudinal studies are needed to establish causal relationships and assess long-term health impacts. Moreover, exploring gene-environment interactions that enhance susceptibility to these chemicals could identify individuals or populations at higher risk.

This study provides compelling evidence that Benzophenone-3 and Propyl Paraben significantly mediate the relationship between phthalate exposure and metabolic changes, unveiling new dimensions of the metabolic disruption caused by environmental contaminants. These findings emphasize the urgent need for continued research and regulatory efforts to address and mitigate the impacts of these widespread environmental chemicals on public health.

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/overview.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

Balakrishnan B, Henare K, Thorstensen EB, Ponnampalam AP, Mitchell MD. (2017). Transfer of bisphenol A across the human placenta. American Journal of Obstetrics & Gynecology, 207(4), 335.e1-335.e8.
Boas M, Feldt-Rasmussen U, Skakkebæk NE, Main KM. Environmental chemicals and thyroid function. Eur J Endocrinol. 2006;154(5):599–611.
Boberg J, Taxvig C, Christiansen S, Hass U. Possible endocrine-disrupting effects of parabens and their metabolites. Reprod Toxicol. 2010;30(2):301–12.
Braun JM, Sathyanarayana S, Hauser R. Phthalate exposure and children's health. Curr Opin Pediatr. 2013;25(2):247–54.
Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S. population to acrylamide in the National Health and Nutrition Examination Survey 2003–2004. Environ Health Perspect. 2008;116(3):384–90.
Darbre PD, Harvey PW. Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J Appl Toxicol. 2008;28(5):561–78.
Genuis SJ, Birkholz D, Chan MG, Brown JD. (2012). Human detoxification of phthalates: a major pathway for removal of plasticizers. Journal of Environmental and Public Health, 2012, 615068.
Gonzalez H, Farbrot A, Larkö O, Wennberg AM. Percutaneous absorption of Benzophenone-3, a common component of topical sunscreens. Clin Exp Dermatol. 2007;27(8):691–4.
Hatch EE, Nelson JW, Qureshi MM, Weinberg J, Moore LL, Singer M, Webster TF. Association of endocrine disruptors and obesity: perspectives from epidemiological studies. Int J Androl. 2008;31(2):194–200.
Herman RA, Evans JJ. Influence of endocrine-disrupting chemicals on the hypothalamic-pituitary-gonadal axis in children. Endocr Dev. 2006;9:118–36.
Janjua NR, Mogensen B, Andersson AM, Petersen JH, Henriksen M, Skakkebaek NE, Wulf HC. Systemic absorption of topical endocrine disruptors in humans. J Eur Acad Dermatol Venereol. 2008;22(2):150–2.
Meeker JD, Sathyanarayana S, Swan SH. Phthalates and other additives in plastics: human exposure and associated health outcomes. Philosophical Trans Royal Soc B: Biol Sci. 2007;364(1526):2097–113.
Ng M, Fleming T, Robinson M. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis. Lancet. 2014;384(9945):766–81.
Saygili E, Kanu SNT, Elibol EB, Topuzoglu A. The assessment of oxidative stress in endometrial tissues of conventional and desflurane-used myomectomies. J Clin Anal Med. 2015;6(5):520–3.
Schmutzler C, Gotthardt I, Hofmann PJ, Radovic B, Kovacs G, Stemmler L, Köhrle J. Endocrine disruptors and the thyroid gland—a combined in vitro and in vivo analysis of potential new biomarkers. Environ Health Perspect. 2004;112(3):338–48.
Vo TT, Jeung EB. An evaluation of estrogenic activities of parabens using uterine calbindin-D9k gene in an immature rat model. Toxicol Sci. 2010;113(1):70–7.
World Health Organization (WHO). (2000). Obesity: preventing and managing the global epidemic. Report of a WHO consultation. WHO Technical Report Series, 894, 1-253.

Table 1

Descriptive analysis of study
Variables	N = 1,669	Median (IQR) or n (%)
Age in years	46	(31, 61)
Gender
Male	845	(51%)
Female	824	(49%)
Race/Ethnicity
Mexican American	290	(17%)
Other Hispanic	152	(9.1%)
Non-Hispanic White	845	(51%)
Non-Hispanic Black	284	(17%)
Other Race - Including Multi-Racial	98	(5.9%)
Income to poverty ratio	1.85	(1.01, 3.88)
Urinary Benzophenone-3 (ng/mL, a sunscreen agent)	13	(4, 66)
Urinary Bisphenol A (ng/mL, a common plastic additive)	1.9	(0.9, 3.7)
Urinary Methyl Paraben (ng/mL, a preservative in cosmetics)	70	(16, 261)
Urinary Ethyl Paraben (ng/mL, another cosmetic preservative)	1	(1, 8)
Urinary Triclosan (ng/mL, an antibacterial agent in personal care products)	10	(3, 51)
Urinary Propyl Paraben (ng/mL, a preservative in cosmetics and pharmaceuticals)	8	(1, 51)
Body Mass Index	28	(24, 32)
Serum Creatinine (mg/dL, a marker of kidney function)	0.86	(0.72, 1.00)
Waist circumference (cm, an indicator of central obesity)	97	(87, 109)

Table 2

Mediation Analysis
Mediator	Effect	Estimate	95% CI Lower	95% CI Upper	P value
Benzophenone-3	ACME	-0.00077	-0.0012	0.001	< 0.001
	ADE	-0.0041	-0.0082	0.001	0.016
	Total Effect	-0.0049	-0.0089	0.001	0.008
	Proportion Med.	0.1554	0.0392	0.44	0.008
Propyl Paraben	ACME	-0.0010	-0.0015	0.001	0.020
	ADE	-0.0039	-0.0078	0.001	0.036
	Total Effect	-0.0049	-0.0089	0.001	0.008
	Proportion Med.	0.2103	0.0192	0.76	0.028

No competing interests reported.

Investigating the Mediating Effects of Urinary Phenols and Parabens on the Relationship Between Phthalate Exposure and Metabolic Changes in Adults

Status:

Version 1

Abstract

Background

1. Introduction

2. Methodology

2.1. Study Sample

2.2. Study Design

2.3. Exposure, Outcome, and Mediators

2.4. Statistical Analysis

3. Results

3.1. Descriptive Result

3.2. Mediation Analysis:

4. Discussion

5. Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Version 1