Elsevier

Chemosphere

Volume 278, September 2021, 130396
Chemosphere

Bisphenol A substitutes and sex hormones in children and adolescents

https://doi.org/10.1016/j.chemosphere.2021.130396Get rights and content

Highlights

  • Urinary bisphenols (BPA/BPF/BPS) were measured in children and adolescents in NHANES.

  • BPA, BPF and BPS had a U-shaped relationship with FAI in female adolescents.

  • BPA, BPF and BPS had an inverse U-shaped relationship with SHBG in female adolescents.

  • BPF and BPS may possess similar endocrine interrupting abilities as BPA.

Abstract

Bisphenol F (BPF) and bisphenol S (BPS) are increasingly used as bisphenol A (BPA) substitutes in consumer products. Little is known about the effects of BPA substitutes on reproductive endocrine function in children and adolescents. Thus, we conducted a cross-sectional study to examine the associations of BPA, BPF, and BPS with sex steroid hormones among 6-19-year old participants. Included were 1317 participants with information on BPA, BPF, BPS, and serum sex hormones [total testosterone (TT), estradiol (E2), and sex hormone binding globulin (SHBG)]. Multiple linear regression accounting for complex survey design was used to assess the association between bisphenols and sex hormones by sex-age groups. Exposure-response (ER) relationships were examined via restricted cubic splines. Significant association with BPF or BPS was sporadic, but BPA presented inverse association with the free androgen index (FAI, calculated as the ratio of TT to SHBG) and E2 and positive association with SHBG and TT/E2 in female adolescents. Further exploration of ER relationships showed that BPA (P for non-linearity = 0.03), BPF (P for non-linearity = 0.005), and BPS (P for non-linearity = 0.08) had a U-shaped relationship with FAI among female adolescents. Additionally, an inverse U-shaped curve was observed for BPA (P for non-linearity = 0.03), BPS (P for non-linearity = 0.01), and BPF (P for non-linearity = 0.01) with SHBG. The associations were virtually nonsignificant among males. Our study demonstrated that BPS and BPF may possess similar endocrine interrupting abilities as BPA.

Introduction

Bisphenol A [BPA, 4,4’-(propane-2,2-diyl) diphenol] is one of the most produced industrial chemicals as the base material for the manufacturing of polycarbonate plastics and epoxy resins (Chen et al., 2016; Rochester and Bolden, 2015; Vandenberg et al., 2007). Human exposure to BPA mainly via dietary intake, ingestion of household dust, and dermal contact with personal care products (Geens et al., 2012). Compelling evidence has documented the deleterious effects of BPA on endocrine function and reproductive health as well as the adverse effects on the cardio-metabolic system in humans (Lang et al., 2008; Minguez-Alarcon et al., 2016; Peretz et al., 2014; Ziv-Gal and Flaws, 2016). In this regard, restrictions and legislations of BPA use have been proposed in BPA-related products like plastic bottles. Canada and the European Union posted a ban on the use of BPA in infant feeding bottles in 2010 (Government of Canada, 2010) and 2011 (The European Commission, 2011), respectively. The U.S. Food and Drug Administration banned the use of BPA-based baby bottles and sippy cups in 2012 (Food and Drug Administration, 2012), with a further prohibition in the coatings of infant formula packaging in 2013 (Food and Drug Administration, 2013). Accordingly, such action has stimulated the introduction of structural analogs such as bisphenol F (BPF), bisphenol S (BPS), bisphenol AF (BPAF), bisphenol P (BPP), bisphenol Z (BPZ), and bisphenol AP (BPAP) as alternatives of BPA in numerous applications (Usman and Ahmad, 2016).

Among the replacements, BPF and BPS are the two main substitutes of BPA (Chen et al., 2016; Eladak et al., 2015; Rochester and Bolden, 2015; Usman and Ahmad, 2016). Specifically, BPS has become a frequently used BPA replacement because of its higher thermal stability (Skledar and Masic, 2016). An increasing number of studies reported that BPS, BPF, and the other BPA analogs are increasingly detected in household dust, drinking water, and foodstuffs worldwide (Chen et al., 2016; Qiu et al., 2019; Zhang et al., 2019). Recent monitoring data from the National Health and Nutrition Examination Survey (NHANES) 2013–2014 revealed that exposure of the general U.S. population to BPA and its substitutes is ubiquitous, with BPA, BPS and BPF detected in 95.7%, 89.4%, and 66.5% of selected urine samples (Lehmler et al., 2018).

Due to the similar chemical structure to BPA (Fig. 1), BPF and BPS may also possess similar endocrine disruption properties, affecting the steroidogenesis process and reproductive health in humans (Rochester and Bolden, 2015). To date, several comprehensive reviews based on in vivo and in vitro studies have concluded that BPS and BPF might have the potencies of anti-androgenic, estrogenic, androgenic, and anti-estrogenic on the same order of magnitude and of similar actions as BPA (Chen et al., 2016; Rochester and Bolden, 2015; Skledar and Masic, 2016). Moreover, experimental studies suggested that exposure to BPS or BPF can lead to BPA-like endocrine alterations in rats, including significant changes in plasma levels of steroid hormones (e.g., testosterone and estradiol) and gonadotropins (e.g., luteinizing hormone and follicle stimulating hormone) (Ahsan et al., 2018; Ullah et al., 2018a, 2018b).

However, little is known on the effects of BPF and BPS exposure on human reproductive endocrine function, especially in children and adolescents. Therefore, we examined the associations of BPA, BPF, and BPS with sex hormones in children and adolescents in a nationally representative population.

Section snippets

Study population

The NHANES is an ongoing national survey program that began in early 1999 with 2-year data releases. The NHANES uses a complex, stratified, clustered four-stage (primary sampling units-segments within primary sampling units-dwelling units-individuals) sampling design to provide information on the health and nutritional status of the noninstitutionalized civilian resident population.

A home interview was first conducted to collect person-level information on demographic, health and nutrition. A

Descriptive statistics

Table 1 presents the population characteristics of 1317 participants in the current analyses. The mean age was 13 years old. Serum TT and SHBG were detected in >90% and 100% of the samples overall (Table S1). Serum E2 was detected in 68.8% of the samples in the whole population. The detectable rates of E2 were less than 50% in 6–11-year-old children and, thus, was not considered further in this subgroup. The detection frequencies of BPA, BPS and BPF were 97.8%, 88.4%, and 54.8%, respectively.

Discussion

This study assessed the associations of BPA and its analogs with sex hormones in children and adolescents. We found that BPA, BPS, and BPF showed a suggestive U-shaped association with FAI in female adolescents. In contrast, inverse U-shaped associations of BPA, BPS, BPF and SHBG were observed in female adolescents. These results were robust to the mutual adjustment of these three bisphenols.

The delicate balance between androgen and estrogen levels and adequate androgen in female adolescents

Conclusion

We found that BPF, BPS, together with BPA, presented significant U-shaped associations with FAI as well as inverse U-shaped relationships with SHBG in female adolescents. No consistent results were detected among male counterparts. The current study is an exploration of the potential reproductive health impacts of BPA and its substitutes among children and adolescents. The endocrine disruption potencies of BPS and BPF deserves further investigation.

Credit roles

Yuqing Wang, Conceptualization, Methodology, Writing – original draft. Ruxianguli Aimuzi, Resources, Methodology, Visualization. Yu Zhang, Resources, Investigation. Min Nian, Resources, Investigation. Kai Luo, Conceptualization, Methodology, Supervision, Writing – review & editing. Jun Zhang, Conceptualization, Methodology, Supervision, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This study was partly funded by the National Natural Science Foundation of China (41991314 and 81530086) and the Collaborative Innovation Program of the Shanghai Municipal Health Commission (2020CXJQ01).

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