Daily Bisphenol A Excretion and Associations With Sex Hormone Concentrations
Daily Bisphenol A Excretion and Associations With Sex Hormone Concentrations
Background: Bisphenol A (BPA) is a high production volume chemical widely used in packaging for food and beverages. Numerous studies have demonstrated that BPA can alter endocrine function in animals, yet human studies remain limited.
Objective: We estimated daily excretion of BPA among adults and examined hypothesized associations with serum estrogen and testosterone concentrations.
Methods: We conducted cross-sectional analyses using data from the InCHIANTI Study, a prospective population-based study of Italian adults. Our study included 715 adults between 20 and 74 years old. BPA concentrations were measured by liquid chromatography–mass spectrometry in 24-hr urine samples. The main outcome measures were serum concentrations of total testosterone and 17β-estradiol.
Results: Geometric mean urinary BPA concentration was 3.59 ng/mL [95% confidence interval (CI), 3.42–3.77 ng/mL], and mean excretion was 5.63 μg/day (5th population percentile, 2.1 μg/day; 95th percentile, 16.4 μg/day). We found higher excretion rates among men, younger respondents, and those with increasing waist circumference (p = 0.013) and weight (p = 0.003). Higher daily BPA excretion was associated with higher total testosterone concentrations in men, in models adjusted for age and study site (p = 0.044), and in models additionally adjusted for smoking, measures of obesity, and urinary creatinine concentrations (β = 0.046; 95% CI, 0.015–0.076; p = 0.004). We found no associations with the other serum measures. We also found no associations with the primary outcomes among women, but we did find an association between BPA and SHBG concentrations in the 60 premenopausal women.
Conclusion: Higher BPA exposure may be associated with endocrine changes in men. The mechanisms involved in the observed cross-sectional association with total testosterone concentrations need to be clarified.
Bisphenol A (BPA) is a synthetic compound that is a suspected endocrine disruptor—a compound capable of causing dysfunction to hormonally regulated body systems (Talsness et al. 2009). BPA is used as a monomer in polycarbonate plastics and in the epoxy resins that are used to line food and beverage containers; it is one of the world's highest production volume chemicals (Burridge 2003). Widespread and continuous daily exposure to BPA is believed to occur primarily through the diet (Stahlhut et al. 2009), as well as from drinking water, dental sealants, dermal exposure, and inhalation of household dusts. The presence of measurable concentrations of metabolites has been reported in the urine of > 90% of people in population-representative samples from across the globe (Calafat et al. 2008; Vandenberg 2007).
Most studies of the health effects of BPA have focused on its well-documented estrogenic activity, with reports of both estrogen agonist (Lee et al. 2003) and androgen antagonist activity (Bonefeld-Jørgensen et al. 2007; Lee et al. 2003; Okada et al. 2008). Suppression of aromatase activity has been observed in laboratory studies (Bonefeld-Jørgensen et al. 2007), as has binding to alternative nuclear receptors, including the aryl hydrocarbon receptor (Kruger et al. 2008) and estrogen-related receptor γ, the function of which remains unknown (Okada et al. 2008). In addition, BPA has been reported to cause thyroid hormone disruption (Moriyama et al. 2002), altered pancreatic beta-cell function (Ropero et al. 2008), and obesity-promoting effects (Newbold et al. 2008). The potential for low-dose effects has prompted debate on revising the current legislation of recommended safe daily exposure levels (Beronius et al. 2010; vom Saal et al. 2007).
Based on the animal and laboratory evidence, we previously hypothesized that higher urinary BPA concentrations would be associated with adverse human health effects. Using data from the U.S. National Health and Nutrition Examination Survey (NHANES) for 2003–2004, the first large-scale population-based epidemiological data on urinary BPA concentrations with sufficient power to detect low-dose effects, we showed for the first time a clear correlation between BPA exposure and disease in humans (Lang et al. 2008). Higher BPA concentrations in NHANES respondents were associated with diagnoses of cardiovascular disease and diabetes but not with other common diseases, which suggested specificity of the reported findings (Melzer et al. 2008, 2009). We recently used an entirely new study sample from the 2005–2006 NHANES to conduct an independent replication of the association of BPA and cardiovascular disease (Melzer et al. 2010). The results of this replication indicated that chance was an implausible explanation for our results.
Studies to clarify the mechanisms of these associations are clearly a priority. A substantive literature documents the disruption of circulating reproductive hormone concentrations after BPA exposures in animal models (reviewed by Richter et al. 2007; see also Bonefeld-Jørgensen et al. 2007; Goodman et al. 2009; Talsness et al. 2009). Studies of human populations have until now been limited to very small sample sizes. A significant, positive relationship was reported between circulating androgen concentrations and BPA exposure in a small study of 26 normal women and 47 women with ovarian dysfunction (Takeuchi et al. 2004). More recently, Meeker et al. (2010) studied serum thyroid and reproductive hormone levels in 167 men recruited through an infertility clinic and observed inverse relationships between urinary BPA concentrations and the free androgen index [ratio of testosterone to sex hormone–binding globulin (SHBG)], estradiol, and thyroid-stimulating hormone. Given these findings, we hypothesized that higher urinary BPA concentrations would be associated with altered reproductive hormone concentrations in serum. Because a limitation of previous studies has been their reliance on single spot urine samples, we based our current analysis on 24-hr urine collections, to provide a direct measure of daily excretion rates. We selected participants from the InCHIANTI study (Aging in the Chianti Area, Tuscany, Italy), a representive population-based study that was conducted in Chianti, Italy, from September 1998 to March 2000. Our analysis of the data from this sample provides the first report of daily BPA excretion levels in a large European cohort.
Abstract and Introduction
Abstract
Background: Bisphenol A (BPA) is a high production volume chemical widely used in packaging for food and beverages. Numerous studies have demonstrated that BPA can alter endocrine function in animals, yet human studies remain limited.
Objective: We estimated daily excretion of BPA among adults and examined hypothesized associations with serum estrogen and testosterone concentrations.
Methods: We conducted cross-sectional analyses using data from the InCHIANTI Study, a prospective population-based study of Italian adults. Our study included 715 adults between 20 and 74 years old. BPA concentrations were measured by liquid chromatography–mass spectrometry in 24-hr urine samples. The main outcome measures were serum concentrations of total testosterone and 17β-estradiol.
Results: Geometric mean urinary BPA concentration was 3.59 ng/mL [95% confidence interval (CI), 3.42–3.77 ng/mL], and mean excretion was 5.63 μg/day (5th population percentile, 2.1 μg/day; 95th percentile, 16.4 μg/day). We found higher excretion rates among men, younger respondents, and those with increasing waist circumference (p = 0.013) and weight (p = 0.003). Higher daily BPA excretion was associated with higher total testosterone concentrations in men, in models adjusted for age and study site (p = 0.044), and in models additionally adjusted for smoking, measures of obesity, and urinary creatinine concentrations (β = 0.046; 95% CI, 0.015–0.076; p = 0.004). We found no associations with the other serum measures. We also found no associations with the primary outcomes among women, but we did find an association between BPA and SHBG concentrations in the 60 premenopausal women.
Conclusion: Higher BPA exposure may be associated with endocrine changes in men. The mechanisms involved in the observed cross-sectional association with total testosterone concentrations need to be clarified.
Introduction
Bisphenol A (BPA) is a synthetic compound that is a suspected endocrine disruptor—a compound capable of causing dysfunction to hormonally regulated body systems (Talsness et al. 2009). BPA is used as a monomer in polycarbonate plastics and in the epoxy resins that are used to line food and beverage containers; it is one of the world's highest production volume chemicals (Burridge 2003). Widespread and continuous daily exposure to BPA is believed to occur primarily through the diet (Stahlhut et al. 2009), as well as from drinking water, dental sealants, dermal exposure, and inhalation of household dusts. The presence of measurable concentrations of metabolites has been reported in the urine of > 90% of people in population-representative samples from across the globe (Calafat et al. 2008; Vandenberg 2007).
Most studies of the health effects of BPA have focused on its well-documented estrogenic activity, with reports of both estrogen agonist (Lee et al. 2003) and androgen antagonist activity (Bonefeld-Jørgensen et al. 2007; Lee et al. 2003; Okada et al. 2008). Suppression of aromatase activity has been observed in laboratory studies (Bonefeld-Jørgensen et al. 2007), as has binding to alternative nuclear receptors, including the aryl hydrocarbon receptor (Kruger et al. 2008) and estrogen-related receptor γ, the function of which remains unknown (Okada et al. 2008). In addition, BPA has been reported to cause thyroid hormone disruption (Moriyama et al. 2002), altered pancreatic beta-cell function (Ropero et al. 2008), and obesity-promoting effects (Newbold et al. 2008). The potential for low-dose effects has prompted debate on revising the current legislation of recommended safe daily exposure levels (Beronius et al. 2010; vom Saal et al. 2007).
Based on the animal and laboratory evidence, we previously hypothesized that higher urinary BPA concentrations would be associated with adverse human health effects. Using data from the U.S. National Health and Nutrition Examination Survey (NHANES) for 2003–2004, the first large-scale population-based epidemiological data on urinary BPA concentrations with sufficient power to detect low-dose effects, we showed for the first time a clear correlation between BPA exposure and disease in humans (Lang et al. 2008). Higher BPA concentrations in NHANES respondents were associated with diagnoses of cardiovascular disease and diabetes but not with other common diseases, which suggested specificity of the reported findings (Melzer et al. 2008, 2009). We recently used an entirely new study sample from the 2005–2006 NHANES to conduct an independent replication of the association of BPA and cardiovascular disease (Melzer et al. 2010). The results of this replication indicated that chance was an implausible explanation for our results.
Studies to clarify the mechanisms of these associations are clearly a priority. A substantive literature documents the disruption of circulating reproductive hormone concentrations after BPA exposures in animal models (reviewed by Richter et al. 2007; see also Bonefeld-Jørgensen et al. 2007; Goodman et al. 2009; Talsness et al. 2009). Studies of human populations have until now been limited to very small sample sizes. A significant, positive relationship was reported between circulating androgen concentrations and BPA exposure in a small study of 26 normal women and 47 women with ovarian dysfunction (Takeuchi et al. 2004). More recently, Meeker et al. (2010) studied serum thyroid and reproductive hormone levels in 167 men recruited through an infertility clinic and observed inverse relationships between urinary BPA concentrations and the free androgen index [ratio of testosterone to sex hormone–binding globulin (SHBG)], estradiol, and thyroid-stimulating hormone. Given these findings, we hypothesized that higher urinary BPA concentrations would be associated with altered reproductive hormone concentrations in serum. Because a limitation of previous studies has been their reliance on single spot urine samples, we based our current analysis on 24-hr urine collections, to provide a direct measure of daily excretion rates. We selected participants from the InCHIANTI study (Aging in the Chianti Area, Tuscany, Italy), a representive population-based study that was conducted in Chianti, Italy, from September 1998 to March 2000. Our analysis of the data from this sample provides the first report of daily BPA excretion levels in a large European cohort.
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