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Urinary Concentrations of Phthalate Biomarkers and Weight Change Among Postmenopausal Women: a Prospective Cohort Study Mary V

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Urinary Concentrations of Phthalate Biomarkers and Weight Change Among Postmenopausal Women: a Prospective Cohort Study Mary V Díaz Santana et al. Environmental Health (2019) 18:20 https://doi.org/10.1186/s12940-019-0458-6 RESEARCH Open Access Urinary concentrations of phthalate biomarkers and weight change among postmenopausal women: a prospective cohort study Mary V. Díaz Santana1, Susan E. Hankinson1, Carol Bigelow1, Susan R. Sturgeon1, R. Thomas Zoeller2, Lesley Tinker3, Jo Ann E. Manson4, Antonia M. Calafat5, Jaymie R. Meliker6 and Katherine W. Reeves1* Abstract Background: Some phthalates are endocrine disrupting chemicals used as plasticizers in consumer products, and have been associated with obesity in cross-sectional studies, yet prospective evaluations of weight change are lacking. Our objective was to evaluate associations between phthalate biomarker concentrations and weight and weight change among postmenopausal women. Methods: We performed cross-sectional (N = 997) and longitudinal analyses (N = 660) among postmenopausal Women’s Health Initiative participants. We measured 13 phthalate metabolites and creatinine in spot urine samples provided at baseline. Participants’ weight and height measured at in-person clinic visits at baseline, year 3, and year 6 were used to calculate body mass index (BMI). We fit multivariable multinomial logistic regression models to explore cross-sectional associations between each phthalate biomarker and baseline BMI category. We evaluated longitudinal associations between each biomarker and weight change using mixed effects linear regression models. Results: In cross-sectional analyses, urinary concentrations of some biomarkers were positively associated with obesity prevalence (e.g. sum of di (2-ethylhexyl) phthalate metabolites [ΣDEHP] 4th vs 1st quartile OR = 3.29, 95% CI 1.80–6.03 [p trend< 0.001] vs normal). In longitudinal analyses, positive trends with weight gain between baseline and year 3 were observed for mono-(2-ethyl-5-oxohexyl) phthalate, monoethyl phthalate (MEP), mono-hydroxybutyl phthalate, and mono-hydroxyisobutyl phthalate (e.g. + 2.32 kg [95% CI 0.93–3.72] for 4th vs 1st quartile of MEP; p trend < 0.001). No statistically significant associations were observed between biomarkers and weight gain over 6 years. Conclusions: Certain phthalates may contribute to short-term weight gain among postmenopausal women. Keywords: Phthalates, Endocrine disruption, Obesity, Weight change, Postmenopause, Women Introduction cosmetics, food packaging, medications) and are ubiqui- The potential contribution of environmental factors to tous in the environment. Nearly all U.S. residents have obesity is of increasing interest. “Obesogens” describes detectable concentrations of phthalate metabolites in environmental chemicals hypothesized to promote their urine, though concentrations vary widely [1]. Lim- obesity due to altered regulation of adipogenesis and ited in vitro data suggest that certain phthalates may lipid metabolism. Phthalates are endocrine disrupting alter pathways that promote adipogenesis [2, 3], and chemicals present in many consumer products (e.g. thus could impact development of obesity. Scant research evaluating associations between phthal- ate exposure and body weight report inconsistent findings. * Correspondence: [email protected] 1Department of Biostatistics and Epidemiology, University of Massachusetts Some cross-sectional studies report positive associations Amherst, 411 Arnold House, 715 North Pleasant Street, Amherst, MA 01003, between certain phthalate metabolite concentrations and USA body mass index (BMI) and obesity among adult women. Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Díaz Santana et al. Environmental Health (2019) 18:20 Page 2 of 12 Specifically, one cross-sectional study using data from baseline. A nested case-control study of breast cancer the 2007–2010 National Health and Nutrition Examin- within the WHI quantified urinary concentrations of ation Survey (NHANES) reported increased prevalence phthalate metabolite on 419 incident breast cancer cases of obesity associated with higher concentrations of and 838 matched controls selected from among these mono-carboxyoctyl phthalate (MCOP), mono (2-ethyl- bone density substudy participants. Breast cancer cases 5-carboxypentyl) phthalate (MECPP), mono (2-ethyl-5- were selected as all cases of invasive breast carcinoma hydroxyhexyl) phthalate (MEHHP), and the sum of that occurred among these participants after the year 3 di-ethylhexyl phthalate metabolites (ΣDEHP) [4]. A sep- follow-up clinic visit through 2013; controls were arate cross-sectional study using 1999–2004 NHANES matched on enrollment date, length of follow-up, age at data observed increased obesity prevalence associated with enrollment, and WHI study arm with a 1:2 ratio. This mono (2-ethylhexyl) phthalate (MEHP) and mono-butyl analysis includes 997 participants (337 cases, 660 con- phthalate (MBP), yet found borderline significant inverse trols) with complete data available (Fig. 1). The longitu- associations between MECPP, MEHHP, mono (2-ethy- dinal analysis included only participants selected as l-5-oxohexyl) phthalate (MEOHP), ΣDEHP and BMI controls (N = 660) in the parent study, given that weight category [5]. Also, other studies, including one using gain is common following breast cancer treatment [10]. 1999–2002 NHANES data [6] and another within the All participants provided written informed consent Nurses’ Health Study (NHS) and NHS2 cohorts [7], re- upon enrollment into the WHI. The WHI was approved ported inverse cross-sectional associations with MEHP by institutional review boards (IRB) at each clinical [6], MBP [6, 7], mono-benzyl phthalate (MBzP) [7], and center. Additionally IRB approval for the present study mono-isobutyl phthalate (MiBP) [7]. was obtained from the University of Massachusetts Phthalates are rapidly metabolized in the body and Amherst. The involvement of the Centers for Disease excreted in urine, and urinary phthalate metabolite Control and Prevention (CDC) laboratory in the analysis concentrations reflect recent exposures [8]. Therefore, of samples did not constitute engagement in human the observed cross-sectional associations may reflect subjects research. confounding via exposure from sources that are them- selves associated with obesity, as opposed to causal Quantification of urinary phthalate metabolites associations. WHI followed a standard collection, processing, and One prior prospective analysis, among 977 women storage protocol at the three clinical centers that col- aged 32–79 from the Nurses’ Health Study (NHS) and lected urine samples. First morning void urine samples NHS2 [7], reported positive associations with weight were collected at home and processed within 30 min gain for MBzP (+ 0.42 kg/year for 4th vs 1st quartiles) after participants arrived at the clinic. WHI recom- and the sum of butyl phthalate metabolites (MBP and mended, but did not require, the use of phthalate-free MiBP; + 0.34 kg/year for 4th vs 1st quartiles) over a 10 polypropylene urine collection containers; one site used year follow-up period. Weight change was not associated the recommended containers while the composition of with concentrations of ΣDEHP or mono-ethyl phthalate the containers used at the other two clinical centers is (MEP) [7]. unknown. However, all sites used polypropylene centri- Whether phthalates affect weight gain remains an fuge tubes and cryovials for long-term storage. Addition- unanswered, yet critically important, question. We pro- ally, we measured concentrations of metabolites as spectively evaluated associations between 13 phthalate opposed to the parent phthalate, which should reflect metabolites (or their sums) and weight change among endogenous exposure as opposed to contamination. 997 postmenopausal women enrolled in the Women’s Urine samples were centrifuged for 5 min at 1330×g and Health Initiative (WHI). 1.8 mL aliquots were frozen and shipped, packed in dry ice, via overnight FedEx to McKesson Bioservices where Subjects and methods they were stored at − 70 °C. Study population Thirteen phthalate metabolites were measured in baseline We included 1257 postmenopausal women selected for urine samples at the CDC: MEP, MBP, mono-hydroxybutyl a nested case-control study of phthalates and breast phthalate (MHBP), MiBP, mono-hydroxyisobutyl phthalate cancer risk within the WHI. The design of the WHI has (MHiBP), MBzP, mono (3-carboxypropyl) phthalate been reported previously [9]. Briefly, from October 1, (MCPP), MEHP, MEHHP, MEOHP, MECPP, MCOP, and 1993 to December 21, 1998 a total of 161,808 women mono-carboxynonyl phthalate (MCNP). Concentrations of aged 50–79 years were enrolled in the WHI. WHI partic- phthalate metabolites were quantified after enzymatic hy- ipants who were enrolled at three bone density substudy drolysis of the conjugated metabolites followed by on-line sites (Birmingham, AL; Pittsburgh, PA; Tucson/Phoenix, solid phase extraction coupled to high performance
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