Association between prenatal exposure to polybrominated diphenyl ethers and anogenital distance in girls at ages 0–4 years

Highlights

• Higher levels of BDE-99, -100, and ∑₅PBDEs were associated with increased two AGD metrics in girls at ages 0–4 years.

• Higher levels of BDE-47 were associated with AGD_AF in girls at ages 0–4 years.

• A positive association between BDE-153 and AGD_AC at age 4 years was also observed.

Abstract

Anogenital distance (AGD) is a sensitive marker for the effect of in utero hormonal disturbance. However, studies on the associations between prenatal exposure to polybrominated diphenyl ethers (PBDEs), a group of endocrine disruptors, and AGD are limited. We examined the associations between prenatal PBDE exposure and AGD in girls at ages 0–4 years in the Shanghai-Minhang Birth Cohort Study. We measured PBDE in cord plasma collected from 148 girls at birth. Of them, two AGD metrics (AGD_AC: from the anterior surface of the clitoral hood to the center of the anus; AGD_AF: from the posterior end of the fourchette to the center of the anus) were measured in 142, 114, 104 and 120 of girls at birth, 6, 12, and 48 months of age, respectively. Linear regression models and linear mixed models were used to evaluate the associations between PBDE exposure and AGD at ages 0–4 years. We found positive associations of PBDE exposure with AGD_AF and AGD_AC in linear regression models, although some associations only reached significance at 6 and 48 months of age. For AGD_AF, the associations were statistically significant for BDE-47, -99, and −100 at 6 months of age (β = 2.34, 95% CI (0.21, 4.48) for BDE-47; β = 2.21, 95% CI (0.05, 4.36) for BDE-99; β = 2.12, 95% CI (0.01, 4.23) for BDE-100), and for BDE-99 and -100 at 48 months of age (β = 4.49, 95% CI (1.27, 7.71) for BDE-99; β = 5.04, 95% CI (1.87, 8.22) for BDE-100), while statistically significant associations with AGD_AC were only observed for BDE-99, -100, −153, and ∑₅PBDEs at 48 months of age (β = 7.62, 95% CI (2.59, 12.64) for BDE-99; β = 7.04, 95% CI (2.01, 12.07) for BDE-100; β = 5.41, 95% CI (0.45, 10.38) for BDE-153; β = 5.05 mm, 95% CI (0.09, 10.01 for ∑₅PBDEs). A consistent pattern of positive associations between prenatal exposure to PBDEs and AGD was also observed in linear mixed models. The finding provided further insights into the adverse effects of PBDEs on reproductive development at low dose exposure.

Introduction

Polybrominated diphenyl ethers (PBDEs), a class of brominated flame retardants, have been used extensively as additives in manufacturing of polyurethane forms, furniture, car seats, and electronic equipment since 1970s (Darnerud et al., 2001). PBDEs are not covalently bound to product materials, enabling them to leach from material surfaces. Owing to their highly persistent and bio-accumulative nature, PBDEs are ubiquitous in the environment (Vuong et al., 2017). Human exposure to PBDEs is widespread, and studies in pregnant women have found detectable levels of PBDEs in the vast majority of the participants (Oulhote et al., 2018; Vuong et al., 2018). Concerns about the health effects of prenatal exposure to PBDEs on fetus have been raised since they can readily cross the placenta to enter fetal circulation (Mazdai et al., 2003).

Previous studies have demonstrated that PBDEs may exhibit estrogenic (Dang et al., 2007b; Meerts et al., 2001), anti-estrogenic (Meerts et al., 2001), and anti-androgenic properties (Stoker et al., 2005), depending on different congeners. Animal studies have indicated that prenatal PBDE exposure was associated with decrease in serum estradiol concentrations (Kim et al., 2009; Talsness et al., 2008), decrease in the number of ovarian follicles (Lilienthal et al., 2006; Talsness et al., 2008) and later onset of puberty in female offspring (Lilienthal et al., 2006; Stoker et al., 2004). Only one human study reported an association between prenatal PBDE exposure and later menarche in girls (Harley et al., 2017). In humans, linking prenatal PBDE exposure to postnatal reproductive end points is challenging due to the long lag between prenatal exposure to PBDEs and the outcomes of interest, like pubertal development, sex steroid levels, and fertility (Barrett et al., 2017).

Anogenital distance (AGD), the distance from the anus to the genital tubercle, is widely accepted as an early indicator of reproductive developmental end points. It has been considered as a life-long readout of endocrine disruption in utero in animal studies (Welsh et al., 2008) and recently in human studies (Priskorn et al., 2018; Thankamony et al., 2016). Moreover, growing evidence shows that AGD correlates with some relevant measures of adult reproductive sequelae in both sexes (Mendiola et al., 2011; Mira-Escolano et al., 2014; Zhou et al., 2016). For example, longer AGD in adult women was associated with higher testosterone levels (Mira-Escolano et al., 2014), increased ovarian follicular number (Mendiola et al., 2012), and higher risk of polycystic ovary syndrome (Sanchez-Ferrer et al., 2017). Lots of literature has reported the associations of prenatal endocrine disrupting chemicals (EDCs) exposure with AGD in boys (Longnecker et al., 2007; Luan et al., 2019; Sun et al., 2018; Swan et al., 2005, 2015; Tian et al., 2019), while the relationship between prenatal EDCs exposure and AGD in girls has received less attention (Barrett et al., 2017; Garcia-Villarino et al., 2018).

For the associations between PBDEs and AGD in girls, only the INMA-Asturias cohort study has explored the associations between prenatal PBDEs exposure and anogenital index (AGI = AGD/subjects’ weight [mm/kg]) and reported null associations in girls at 18 months of age (n = 16) (Garcia-Villarino et al., 2018), and at age 4 years (n = 113) (García-Villarino et al., 2020). With repeated measurements of AGD from birth to 4 years, the present study aimed to examine the associations between prenatal PBDE exposure and AGD in girls at ages 0–4 years, and to attest whether these associations would change over time.