Abstract and Introduction
Abstract
Study Question: Is pre-conception exposure to parabens associated with fecundity in couples of childbearing age?
Summary Answer: Paraben exposure in female partners was associated with reduced couple fecundity and anti-Müllerian hormone (AMH) might be one of the possible mediators.
What is Known Already: The reproductive toxicity of parabens, a class of widely used preservatives, has been suggested but evidence regarding their effects on couple fecundity is scarce.
Study Design, Size, Duration: In this couple-based prospective cohort study, a total of 884 pre-conception couples who participated in the Shanghai Birth Cohort between 2013 and 2015 were included.
Participants/Materials, Setting, Methods: Concentrations of six parabens were measured in urine samples collected from couples. Malondialdehyde, C-reactive protein, and AMH were assessed in female partners. The outcomes included couple fecundability (time-to-pregnancy, TTP) and infertility (TTP > 12 menstrual cycles). Partner-specific and couple-based models were applied to estimate the associations. The joint effect of paraben mixture on couple fecundity was estimated by quantile-based g-computation (q-gcomp). Mediation analysis was used to assess the mediating roles of oxidative stress, inflammation and ovarian reserve.
Main Results and the Role of Chance: A total of 525 couples (59.4%) conceived spontaneously. In the partner-specific model, propyl paraben (PrP), butyl paraben (BuP), and heptyl paraben (HeP) in female partners were associated with reduced fecundability (fecundability odds ratio (95% CI): 0.96 (0.94–0.98) for PrP; 0.90 (0.87–0.94) for BuP; 0.42 (0.28–0.65) for HeP) and increased risk of infertility (rate ratio (95% CI): 1.06 (1.03–1.10) for PrP; 1.14 (1.08–1.21) for BuP; 1.89 (1.26–2.83) for HeP). Similar associations were observed in the couple-based model. AMH played a significant mediation role in the association (average causal mediation effect (95% CI): 0.001 (0.0001–0.003)). Paraben exposure in male partners was not associated with couple fecundity. The joint effect of paraben mixture on couple fecundity was non-significant.
Limitations, Reasons for Caution: Self-reported pregnancy and single urine sample may lead to misclassification. The mediation analysis is limited in that levels of sex hormones were not measured. The inclusion of women with irregular menstrual cycles might affect the results. It is possible that the observed association was due to reverse causation.
Wider Implications of the Findings: This is the first study to assess the effects of paraben exposure on couple fecundity in Asians. Given the widespread exposure to parabens in couples of childbearing age, the present findings may have important public health implications.
Study Funding/Competing Interest(S): This study was supported in part by the National Natural Science Foundation of China (41991314), the Shanghai Science and Technology Development Foundation (22YF1426700), the Science and Technology Commission of Shanghai Municipality (21410713500), and the Shanghai Municipal Health Commission (2020CXJQ01). All authors declare no conflict of interest.
Trial Registration Number: N/A.
Introduction
Parabens are a class of synthetic chemicals known as esters of p-hydroxybenzoic acid. As the most extensively used preservatives, parabens have been applied in foods, drinks, cosmetics, and pharmaceuticals for about 100 years due to the excellent antibacterial and antifungal properties (Soni et al., 2005; Petric et al., 2021). In the late 20th century, parabens were found to have estrogenic potential, raising an initial concern of their safety, but it did not reach the level of revising the safety guidelines (Fransway et al., 2019a). At present, 35 parabens have been identified in consumer products (Fransway et al., 2019b) and the most common parabens are methyl paraben (MeP), ethyl paraben (EtP), propyl paraben (PrP), butyl paraben (BuP), benzyl paraben (BzP), and heptyl paraben (HeP). It is reported that parabens were used in more than 22 000 types of cosmetics (Andersen, 2008). In China, the production of parabens (MeP, EtP, PrP) has exceeded 10 000 tons per month (Wei et al., 2021). This figure is likely to increase because parabens are becoming substitutes for the legacy of benzoic acid and sodium benzoate in the food industry.
Humans are exposed to parabens primarily via dietary ingestion and dermal absorption (Liao et al., 2013; Gao and Kannan, 2020). Parabens have been identified in a number of biological matrices, including blood (Song et al., 2020), urine (Honda et al., 2018), breast milk (Iribarne-Durán et al., 2022), semen (Yu et al., 2021), and placenta (Fernández et al., 2021). Animal studies suggest that parabens have adverse effects on reproduction in the form of xenohormones (Nowak et al., 2018). The estrogenic activity of these chemicals increases with increasing alkyl chain length and branch (HeP > BzP > BuP > PrP > EtP > MeP) (Karwacka et al., 2019). Close attention has been paid to whether paraben exposure may have adverse health effects on human reproduction.
Fecundity is defined as the biologic capacity for conception (Wood, 1994). In the past decades, increased incidences of premature ovarian insufficiency (Rudnicka et al., 2018) and polycystic ovary syndrome (Barthelmess and Naz, 2014), and decreased sperm count and quality (Carlsen et al., 1992) have been reported. Approximately 9% of the global population seeks costly fertility care (Boivin et al., 2007) and infertility has been recognized as a worldwide public health issue. However, the potential reasons for declining fecundity are largely unexplored (Buck Louis, 2014). In addition to the well-known societal changes, it is speculated that environmental endocrine disrupting chemicals (EDCs) may have negative impacts on fecundity (Green et al., 2021). Evidence has shown that the target organs of EDCs, especially ovaries and testicles, may be directly damaged by parabens, leading to adverse effects on follicle growth (Gal et al., 2019), oocyte maturation (Jeong et al., 2020; Meng et al., 2020), spermatogenesis (Maske et al., 2020), and sperm quality (Garcia et al., 2017). Additionally, parabens may indirectly affect the function of gonads and gametes by disrupting the hypothalamic–pituitary–gonadal, HP-adrenal, or HP-thyroid axis, thus reducing fecundity (Hipwell et al., 2019; İnkaya and Barlas, 2022; Liang et al., 2022).
Only one epidemiological study has examined the link between paraben exposure with couple fecundity, measured by time-to-pregnancy (TTP) (Smarr et al., 2017). This prospective cohort study found that higher quartiles of urinary parabens in females were associated with reduced couple fecundity. In addition, the underlying mechanisms remain largely unknown. Oxidative stress has been recognized as one of the main mediators of female infertility (Bhardwaj et al., 2021). Low-grade chronic inflammation is generally blamed for predisposing to infertility (Ozgu-Erdinc et al., 2021). Anti-Müllerian hormone (AMH), a reliable and useful marker of ovarian reserve, has been widely used as a measure of fertility capacity (Kyweluk, 2020). Previous studies have suggested that paraben exposure may result in oxidative damage (Pollack et al., 2020), inflammation (Aung et al., 2019), and diminished ovarian reserve in reproductive age women (Yan et al., 2022). We hypothesize that oxidative stress, inflammation, and ovarian reserve may be mediators in the association between paraben exposure and fecundity.
In this couple-based prospective cohort study, we examined the effects of six parabens on couple fecundity using multiple statistical models. Our objectives were to investigate (i) the associations of individual parabens for each partner with couple fecundity; (ii) the joint effect of paraben mixture on couple fecundity; and (iii) the mediation roles of oxidative stress, inflammation, and ovarian reserve in the associations between female paraben exposure and fecundity.
Hum Reprod. 2023;38(4):726-738. © 2023 Oxford University Press
