Phthalates and Obesity: Examining the Metabolism-disrupting Chemical Hypothesis in Midlife Women

Abstract

The prevalence of obesity and diabetes has increased dramatically in the past century. Because this period coincided with the increasing use of synthetic chemicals in industry and commerce, these chemicals are hypothesized to disrupt metabolism and contribute to the obesity-diabetes twin epidemic.

Phthalates, a class of synthetic chemicals added to numerous consumer and industrial products, are suspected to contribute to obesity, adverse adipokine profiles, and diabetes by interfering with energy and nutrient metabolism. Though supported by mechanistic studies, the epidemiologic evidence on phthalates, obesity, and its metabolic complications in adults is limited. Most studies are cross-sectional and conducted in largely homogeneous populations.

Using data from the Study of Women’s Health Across the Nation, a racially/ethnically diverse group of women with urinary phthalate metabolite data in 1999/2000 and 2002/2003 and longitudinal metabolic outcomes, this dissertation examined the potential metabolic effects of phthalate exposure.

In Aim 1, we examined whether higher phthalate exposure in 1999/2000 was associated with more rapid increases in body weight (BW), fat mass (FM), and body fat percentage (BF%) over 18 years in 1369 women. After adjusting for demographic, lifestyle, and menopause-related factors, except for mono-carboxy-isononyl phthalate, higher urinary concentrations of all phthalate metabolites were associated with more rapid increases in FM and BF%. Per doubling of phthalate metabolite concentrations, differences in five-year BF% change ranged from 0.03 percentage point (ppt) (95% confidence interval (CI): -0.03, 0.09) for mono-isobutyl phthalate to 0.09 ppt (95% CI: 0.02, 0.16) for mono(3-carboxypropyl) phthalate. Results were similar for FM change, but the associations with BW change were mostly null. Stratified analyses by baseline obesity status revealed stronger associations – at magnitudes comparable to some lifestyle risk factors of obesity – among normal/underweight women.

In Aim 2, we examined whether higher phthalate exposure was associated with adverse adipokine profiles characterized by higher leptin levels, lower high-molecular-weight (HMW) adiponectin levels, and a greater ratio between the two in 1250 women. We found that most phthalate metabolites were positively associated with leptin, but the associations were attenuated with adjustment for body mass index (BMI). Further, regardless of BMI adjustment, mono(2-ethylhexyl) phthalate (MEHP) was associated with higher HMW adiponectin levels, while most other phthalate metabolites were not associated with HMW adiponectin. None of the phthalates were positively associated with the leptin:HMW adiponectin ratio upon BMI adjustment, and MEHP was inversely associated with the ratio.

In Aim 3, we examined whether higher phthalate exposure was associated with a higher incidence of diabetes over six years in 1308 women. After adjusting for demographic, lifestyle, and health-related factors, several HMW phthalate metabolites were associated with a higher diabetes incidence, but none of the associations were statistically significant. There was effect modification by race/ethnicity. Among White women, each doubling of the concentrations of mono-isobutyl phthalate, monobenzyl phthalate, mono-carboxyoctyl phthalate, mono-carboxy-isononyl phthalate, and mono(3-carboxypropyl) phthalate was significantly associated with 30-63% higher diabetes incidence. In contrast, none of the phthalate metabolites were associated with diabetes incidence in Black or Asian women.

Overall, phthalate exposure was associated with more rapid body fat increases, but not adverse adipokine profiles independent of BMI. Some phthalates were associated with a higher incidence of diabetes in some women. These findings partially support a role of phthalates in the development of obesity and diabetes, suggesting that limiting phthalate exposure may help prevent obesity and its comorbidities.