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nature publishing group Association of prenatal urinary phthalate metabolite concentrations and childhood BMI and obesity Kim G.

Harley1 , Kimberly Berger1 , Stephen Rauch1 , Katherine Kogut1 , Birgit Claus Henn2 , Antonia M. Calafat3 , Karen Huen1 , Brenda Eskenazi1 and Nina Holland1 BACKGROUND: Although experiments in animals suggest that phthalates may have obesogenic effects, studies on prenatal exposure in children show inconsistent results. METHODS: We measured urinary concentrations of

11 phthalate metabolites collected twice during pregnancy from mothers participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort study (N = 345). Height, weight, waist circumference, and percent body fat were assessed in their children between

5 and

12 years of age. We used generalized estimating equations to examine associations at each age and tested for interaction by sex. RESULTS: Metabolites of diethyl phthalate (DEP), di-n-butyl phthalate (DBP), butyl benzyl phthalate, and di(2-ethylhexyl) phthalate (DEHP) were positively associated with BMI z-score, waist circumference z-score, and percent body fat at multiple ages. At age 12, we observed increased odds of being overweight/obese with each doubling of prenatal concentra- tions of DEP (odds ratio = 1.3;

95% confidence intervals: 1.1, 1.4), DBP (1.2;

1.0, 1.4), and DEHP (1.3;

1.0, 1.6) metabolites. Results were similar in boys and girls except for DBP metabolites and the non-specific metabolite mono-(3-carbox- ypropyl) phthalate, which showed positive associations only in boys. CONCLUSION: In utero exposure to certain phthalates is associated with increased BMI and risk for overweight/obesity in childhood. The prevalence of obesity in children and adults has increased worldwide in recent decades (1), such that 35% of men and 40% of women in the United States are currently obese (2). Evidence suggests that increased caloric intake and reduced physical activity may not be sufficient to explain the current obesity epidemic (3). Exposure to endocrine- disrupting chemicals (EDCs), including phthalates―a class of chemicals widely used in personal care products, fragrances, medication coatings, adhesives, and polychlori- nated vinyl (PVC) plastics―has been hypothesized as a possible contributor to the etiology of obesity (4). The prenatal period may be a critical developmental window for exposure to obesogenic chemicals to impact BMI later in life (5). Exposure to phthalates is almost ubiquitous, with metabo- lites of eight common phthalates (Table 1) detected in 94% or more of Americans participating in the 2001C2010 cycles of the National Health and Nutrition Examination Survey (NHANES) (6). Low-molecular-weight phthalates, including diethyl phthalate (DEP), di-n-butyl phthalate (DBP), and di- isobutyl phthalate (DiBP), are used in personal care products as carriers for fragrance and in the coatings of some medications. High-molecular-weight phthalates, including butyl benzyl phthalate (BBzP), di(2-ethylhexyl) phthalate (DEHP), and di-isononyl phthalate (DiNP), are used to soften plastics, particularly PVC building materials. These phthalates break down into monoester metabolites that are eliminated in urine. Several phthalates, including the metabolites of DBP, BBzP, and DEHP, have been shown to bind to and activate peroxisome proliferator-activated receptor-alpha (PPAR-α) and -gamma (PPAR-γ), nuclear receptors involved in fatty acid oxidation, adipogenesis, and fat storage (7). DEHP has also been associated with reduced thyroid hormone levels in rodent studies, which may interrupt energy homeostasis and increase body fat (8). Much of the rodent research focuses on DEHP, whereas other phthalates have been less studied with regard to body weight. Studies on adult male (8) and female (9) mice show that exposure to DEHP at doses ranging from 0.05 mg/kg per day (similar to occupational exposure levels) to

500 mg/kg per day were associated with increased food intake, body weight, and visceral fat. Prenatal and lactational exposure to DEHP at doses ranging from 0.05 to

300 mg/kg per day has also been associated with increased body weight and fat mass (9,10), which may not manifest until the animal reaches adulthood. For example, in male rat offspring, prenatal and lactational exposure of dams to

300 mg/kg per day of DEHP was associated with decreased body weight at birth but with significantly higher body weight at

1 Center for Environmental Research and Children'

s Health (CERCH), School of Public Health, University of California, Berkeley, CA;

2 Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts;

3 Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia. Correspondence: Kim G. Harley ([email protected]) Received

19 January 2017;

accepted

4 April 2017;

advance online publication

31 May 2017. doi:10.1038/pr.2017.112 Copyright ?

2017 International Pediatric Research Foundation, Inc. Volume

82 | Number

3 | September

2017 Pediatric RESEARCH

405 Population Study | Articles puberty and adulthood in the exposed group compared with controls (10). Cross-sectional studies in humans have also linked urinary metabolites of various phthalates to increased BMI, waist circumference, and obesity........