Thyroid hormone parameters during pregnancy in relation to urinary bisphenol A concentrations: A repeated measures study☆
Introduction
Although regulations have increasingly restricted the production and use of bisphenol A (BPA) in several consumer products made of polycarbonate plastics (National Conference of State Legislature, 2015), there is continuing evidence that widespread exposure to BPA still exists in the U.S. population (Andra et al., 2015). Furthermore, previous human exposure studies have shown detectable levels of urinary BPA in a majority of pregnant women in the U.S. (Braun et al., 2011, Woodruff et al., 2011). Human exposure to BPA has been hypothesized to disrupt critical hormones in the endocrine system (Vandenberg et al., 2012). There are several animal and in-vitro studies providing evidence that BPA exposure can affect biochemical processes that disrupt the production, secretion, or circulation of thyroid hormones (Boas et al., 2012, Richter et al., 2007, Tilley and Fry, 2015).
Within the hypothalamic-pituitary-thyroid (HPT) axis, thyrotropin (TSH) – a glycoprotein hormone originating from the pituitary gland – stimulates the thyroid gland to produce the thyroid hormones triiodothyronin (T3), and thyroxine (T4) (Tingi et al., 2016). T3 and T4 circulate throughout the body to affect target sites, in addition to negatively regulating TSH production at the pituitary gland (Tingi et al., 2016). Homeostatic regulation of the HPT axis during gestation is critical for the developing fetus, and maternal thyroid hormone levels have varying impacts on the fetus throughout periods of gestation (Tingi et al., 2016). During the first 10–12 weeks of gestation, the fetus's entire supply of thyroid hormones comes from the mother, and coincides with fetal neurodevelopmental events such as brain stem and cerebral neurogenesis (Moog et al., 2017, Préau et al., 2015). After this period, the fetal thyroid gland begins to mature and produce thyroid hormones, but is not fully functional until 18–20 weeks gestation (Moog et al., 2017, Tingi et al., 2016). Maternal thyroid hormones also affect the maturation of various other tissues and organs in the fetus, in addition to stimulating the placental secretion of hormones that influence the supply of fetal glucose (Moog et al., 2017, Vissenberg et al., 2015).
Thyroid disease states such as hyperthyroidism and hypothyroidism are associated with adverse health outcomes during pregnancy (Institute of Medicine, 2007, Krassas et al., 2010, Neale and Burrow, 2004), and associated with stillbirth, miscarriage, preeclampsia, preterm delivery, cardiovascular disorders, and neurodevelopmental disorders in fetuses (Haddow et al., 1999, Luewan et al., 2011, Männistö et al., 2013). In addition to overt thyroid disease, subclinical perturbations of thyroid hormone levels are also suspected of adversely affecting child and maternal health during pregnancy (Negro and Mestman, 2011). Recent review articles and meta-analyses suggest that subclinical hypothyroidism is associated with a higher risk for pre-eclampsia, pregnancy loss, placental abruption, premature rupture of membranes, preterm delivery, and neonatal mortality (Maraka et al., 2016, Tingi et al., 2016, van den Boogaard et al., 2011). These findings emphasize the need to continue investigating potential causes and consequences of changes in subclinical thyroid hormone levels during pregnancy.
Of particular relevance to child and maternal health are the interactions between BPA and thyroid hormones during pregnancy. Human health studies that examined BPA and thyroid hormones in adults (Geens et al., 2015, Meeker et al., 2009a, Meeker and Ferguson, 2011, Sriphrapradang et al., 2013, Wang et al., 2012, Wang et al., 2013), and in pregnant women (Chevrier et al., 2013, Romano et al., 2015), have provided evidence suggesting that BPA may affect circulating levels of several thyroid hormone parameters. One of the studies of pregnant women indicated that maternal BPA levels were inversely associated with total T4 (Chevrier et al., 2013), whereas the other study did not show significant relationships between maternal BPA and any of the thyroid hormone parameters measured (Romano et al., 2015). Some of these studies were limited by collection of only a single spot urine and/or blood sample for measurement of BPA and thyroid hormones, having a relatively small sample size, or assessing associations with only a cross-sectional design. Our study is the first to examine this relationship in repeated measurements during pregnancy, which not only provides greater statistical power to assess a more robust exposure assessment, but also characterizes associations between BPA and thyroid hormones across time during gestation by controlling for individual variability. Specifically in our current study, we evaluated the associations between four repeated measures of urinary BPA and plasma thyroid hormone parameters – TSH, total T3, and free and total T4 – collected at up to four study visits in pregnancy. We also sought to identify potential windows of vulnerability during pregnancy by assessing the extent to which these associations varied by gestational age.
Section snippets
Study population
Participants of this current study comprised a subset of pregnant women drawn from a nested case-control study who were initially recruited for a prospective, longitudinal birth cohort at the Brigham and Women's Hospital in Boston, MA (Ferguson et al., 2014a, Ferguson et al., 2015). In previous studies of this cohort, exposures to environmental phthalates and health outcomes such as preterm birth were investigated (Ferguson et al., 2014b), in addition to markers of thyroid function (Johns et
Results
Previous studies of this case-control study population have characterized distributions of BPA and thyroid hormone levels by study visit of sample collection (Cantonwine et al., 2015, Johns et al., 2016). The overall detection rate of BPA in our study sample was 81.1%. Geometric means and standard deviations for all thyroid hormones by study visit were calculated and presented in a previous study (Johns et al., 2016). In Table 1, we present selected percentiles of BPA concentrations by
Discussion
To our knowledge, this is the first epidemiological study to assess the associations between repeated measures of BPA and maternal thyroid hormone parameters in pregnancy. Using repeated measures, our analysis demonstrated that urinary BPA concentrations were inversely associated with levels of TSH in pregnant women and positively associated with free T4. In our stratified analyses, BPA was significantly inversely associated with TSH at visits 3 and 4. BPA was also marginally associated with
Conclusions
In summary, the present study provides further evidence that BPA exposure has the potential to disrupt thyroid hormones in humans. In order to elucidate the mechanisms that may explain these associations, further animal and human studies must be conducted. Given that pregnancy is an especially vulnerable period of time for fetal development and maternal health, it is important to continue advancing our knowledge of the toxicological effects of environmental exposures during pregnancy. Future
Funding
Subject recruitment and sample collection was originally funded by Abbott Diagnostics.
This work was also supported by the National Institute of Environmental Health Sciences, National Institutes of Health (grants R01ES018872, P42ES017198, P01ES022844, P30ES017885, P50ES026049, and T32ES007062).
Support for Max Aung was provided in part by a grant from the Robert Wood Johnson Foundation Health Policy Research Scholars program.
Support for Kelly Ferguson was provided in part by the Intramural
Acknowledgements
We thank K. Kneen, S. Clipper, G. Pace, D. Weller, and J. Bell of NSF International in Ann Arbor, Michigan, for urine BPA analysis; D. McConnell of the CLASS Lab at University of Michigan for assistance in hormone analysis.
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The authors declare they have no actual or potential competing financial interests.