Non-persistent endocrine disrupting chemical mixtures and uterine leiomyomata in the study of environment, lifestyle and fibroids (SELF)

Abstract

Background: Results of studies investigating associations between individual endocrine-disrupting chemicals (EDCs) and incidence of uterine leiomyomata (UL), a hormone-dependent gynecological condition, have been inconsistent. However, few studies have evaluated simultaneous exposure to a mixture of EDCs with UL incidence.

Methods: We conducted a case-cohort analysis (n = 708) of data from the Study of the Environment, Lifestyle and Fibroids (SELF), a prospective cohort study. Participants were aged 23-35 years at enrollment, had an intact uterus, and identified as Black or African American. We measured biomarker concentrations of 21 non-persistent EDCs, including phthalates, phenols, parabens, and triclocarban, in urine collected at baseline, 20-month, and 40-month clinic visits. We ascertained UL incidence and characteristics using ultrasounds at baseline and approximately every 20 months through 60 months. We used probit Bayesian Kernel Machine Regression (BKMR-P) to evaluate joint associations between EDC mixtures with cumulative UL incidence. We estimated the mean difference in the probit of UL incidence over the study period, adjusting for baseline age, education, years since last birth, parity, smoking status and body mass index. We converted probit estimates to odds ratios for ease of interpretation.

Results: We observed that urinary concentrations of the overall EDC mixture were inversely associated with UL incidence in the overall mixtures model, with the strongest inverse associations at the 70th percentile of all biomarkers compared with their 50th percentile (odds ratio = 0.59; 95% confidence interval: 0.36, 0.96). Strongest contributors to the joint association for the mixture were bisphenol S (BPS), ethyl paraben (EPB), bisphenol F (BPF) and mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), which each demonstrated inverse associations except for MECPP. There was suggestive evidence of an interaction between MECPP and EPB.

Conclusion: In this prospective ultrasound study, we observed evidence of an inverse association between the overall mixture of urinary biomarker concentrations of non-persistent EDCs with UL incidence.

Keywords: Biomarkers; Endocrine disrupting chemicals; Environmental exposures; Epidemiology; Mixtures; Reproductive health.

Figure 1.

Spearman correlation matrix for log-transformed non-persistent chemical mixture, cumulatively averaged concentrations (21 chemicals). Abbreviations: Bisphenol A (BPA), Bisphenol F (BPF), Bisphenol S (BPS), Benzophenone-3 (BP3), Triclosan (TCS), Triclocarban (TCC), Butylparaben (BPB), Ethylparaben (EPB), Methylparaben (MPB), Propylparaben (PPB), Mono-n-butyl phthalate (MBP/MNBP), Mono-isobutyl phthalate (MiBP), Monobenzyl phthalate (MBZP), Mono-2-ethylhexyl phthalate (MEHP), Mono-2-ethyl-5-carboxypentyl phthalate (MECPP), Monoethyl phthalate (MEP), Mono carboxyisooctyl phthalate (MCOP), Mono-isononyl phthalate (MNP/MINP), Mono carboxyisononyl phthalate (MCNP), Mono-3-carboxypropyl phthalate (MCPP), 2,5-dichlorophenol (DCP25). (color figure)

Figure 2.

Overall association of the EDC metabolite mixture with UL (mean difference in the probit of UL and 95% credible intervals) when all chemical biomarker concentrations are at a particular quantile, compared to when all biomarker concentrations are at their 50th percentiles. Model adjusted for age, education, years since last birth, parity, smoking status, and BMI. Biomarker concentrations are ln-transformed and z-scored based on biomarker concentrations averaged over baseline, 20-month and 40-month visits. Biomarkers included in the model: Bisphenol A (BPA), Bisphenol F (BPF), Bisphenol S (BPS), Benzophenone-3 (BP3), Triclosan (TCS), Triclocarban (TCC), Butylparaben (BPB), Ethylparaben (EPB), Methylparaben (MPB), Propylparaben (PPB), Mono-n-butyl phthalate (MBP/MNBP), Mono-isobutyl phthalate (MiBP), Monobenzyl phthalate (MBZP), Mono-2-ethylhexyl phthalate (MEHP), Mono-2-ethyl-5-carboxypentyl phthalate (MECPP), Monoethyl phthalate (MEP), Mono carboxyisooctyl phthalate (MCOP), Mono-isononyl phthalate (MNP/MINP), Mono carboxyisononyl phthalate (MCNP), Mono-3-carboxypropyl phthalate (MCPP), 2,5-dichlorophenol (DCP25).

Figure 3.

Posterior Inclusion Probabilities (PIPs) from a Probit Bayesian kernel machine regression (BKMR-P) model for associations between an EDC metabolite mixture and mean difference in the probit of UL. Biomarkers included in the model (based on metabolites averaged over baseline, 20-month and 40-month visits): Bisphenol A (BPA), Bisphenol F (BPF), Bisphenol S (BPS), Benzophenone-3 (BP3), Triclosan (TCS), Triclocarban (TCC), 2,5-dichlorophenol (25 DCP), Butylparaben (BPB), Ethylparaben (EPB), Methylparaben (MPB), Propylparaben (PPB), Mono-n-butyl phthalate (MBP/MNBP), Mono-isobutyl phthalate (MiBP), Monobenzyl phthalate (MBZP), Mono-2-ethylhexyl phthalate (MEHP), Mono-2-ethyl-5-carboxypentyl phthalate (MECPP), Monoethyl phthalate (MEP), Mono carboxyisooctyl phthalate (MCOP), Mono-isononyl phthalate (MNP/MINP), Mono carboxyisononyl phthalate (MCNP), Mono-3-carboxypropyl phthalate (MCPP).

Figure 4.

Exposure-response functions representing associations between a given biomarker concentrations and mean difference in the probit of UL (with 95% credible intervals), when all other biomarkers are at their 50^th percentiles. Model adjusted for age, education, years since last birth, parity, smoking status, and BMI. Biomarker concentrations are ln-transformed and z-scored. Biomarkers included in the model (averaged over baseline, 20-month and 40-month visits): Bisphenol A (BPA), Bisphenol F (BPF), Bisphenol S (BPS), Benzophenone-3 (BP3), Triclosan (TCS), Triclocarban (TCC), 2,5-dichlorophenol (25 DCP), Butylparaben (BPB), Ethylparaben (EPB), Methylparaben (MPB), Propylparaben (PPB), Mono-n-butyl phthalate (MBP/MNBP), Mono-isobutyl phthalate (MiBP), Monobenzyl phthalate (MBZP), Mono-2-ethylhexyl phthalate (MEHP), Mono-2-ethyl-5-carboxypentyl phthalate (MECPP), Monoethyl phthalate (MEP), Mono carboxyisooctyl phthalate (MCOP), Mono-isononyl phthalate (MNP/MINP), Mono carboxyisononyl phthalate (MCNP), Mono-3-carboxypropyl phthalate (MCPP).

Figure 5.

Mean difference in the probit of UL for an increase from the 25^th to 75^th percentile of an individual biomarker, when all other biomarkers in the mixture are fixed to the 25th, 50th, and 75th percentiles. Model adjusted for age, education, years since last birth, parity, smoking status, and BMI. Biomarker concentrations are ln-transformed and z-scored.