Associations of perfluoroalkyl and polyfluoroalkyl substances (PFAS) and PFAS mixtures with adipokines in midlife women
Introduction
The global epidemic of overweight and obesity presents a major challenge to chronic disease prevention across the life course (Afshin et al., 2017). While the role of many modifiable risk factors for obesity including high caloric diet and sedentary lifestyle have been widely studied, the role of environmental factors is beginning to receive attention. One factor of interest is perfluoroalkyl and polyfluoroalkyl substances (PFAS), a family of synthetic chemicals with ubiquitous human exposure (ATSDR, 2018). PFAS have been used in many consumer products including upholstery, non-stick cookware, food packaging, personal care products, and fire-fighting foams (ATSDR, 2018). A recent nationwide survey reported that more than 200 million United States residents could have PFAS-contaminated drinking water (Andrews and Naidenko, 2020). In addition, PFAS are extremely stable in the environment and some have long elimination half-lives in humans (Ding et al., 2020a; Olsen et al., 2007).
Previous epidemiologic studies suggest that PFAS may impact metabolic function (Cardenas et al., 2018; Ding et al., 2021; Liu et al., 2018), alter glucose homeostasis (Cardenas et al, 2017, 2019; Sun et al., 2018), and affect lipid metabolism (Eriksen et al., 2013; Lin et al., 2019; Starling et al., 2014). PFAS were also found to promote murine adipogenesis and trigger adipocyte differentiation of human adipose tissues and their derived stem cells in vitro (Liu et al., 2019; Watkins et al., 2015; Xu et al., 2016). Growing evidence supports obesity as a disorder of energy homeostasis rather than simple accumulation of excess adiposity (Schwartz et al., 2017). To evaluate whether PFAS may increase the risk of obesity-related disorders and understand the etiology, examining the effects of PFAS on key regulatory factors of human adipose tissue is critically important.
Adipose tissue serves as an active endocrine organ and secretes multiple hormone-like adipokines such as leptin and adiponectin to modulate metabolic processes (Ouchi et al., 2011). Leptin, a key pro-inflammatory adipokine, is expressed proportionately to body fat mass and is positively associated with control of appetite and energy homeostasis (Watkins et al., 2015). Despite this, most individuals with obesity have elevated leptin concentrations in circulating and active forms, indicating a state of leptin resistance (Lee et al., 2009). Soluble leptin receptor (sOB-R) can downregulate the action of leptin through the formation of leptin-sOB-R complexes (Lammert et al., 2001). The free leptin index (FLI), the ratio of total leptin to sOB-R concentrations, has been proposed as a biomarker of leptin resistance to give information on leptin bioavailability (Kratzsch et al., 2002). As opposed to leptin, serum adiponectin correlates inversely with fat mass and insulin resistance and exerts anti-inflammatory effects (Watkins et al., 2015). The high molecular weight (HMW) isoform of adiponectin is the most biologically active, compared to its low and middle molecular weight counterparts (Ouchi et al., 2011).
The impact of PFAS on adipokines is not well understood. Among the limited number of epidemiologic studies of the association between PFAS and adipokines (Bassler et al., 2019; Cardenas et al., 2017; Lin et al., 2011; Liu et al., 2018) findings are inconsistent. Their small sample size may also limit the power to observe associations. Additionally, people are exposed to multiple PFAS on a daily basis, but all previous studies focused on individual compounds. Studies of chemicals assessed individually are subject to non-linear dose-response relationships and confounding by co-exposure (Ding et al., 2020b; Wang et al, 2018, 2019b, 2020b). Furthermore, it is largely unknown whether the menopausal transition, which is accompanied by unfavorable changes in body composition and abdominal fat deposition (Greendale et al., 2019), may be involved in the potential effects of PFAS on metabolic disorders.
Therefore, we examined associations between PFAS concentrations and leptin, sOB-R, adiponectin, and HMW adiponectin in the Study of Women's Health Across the Nation (SWAN), a large, prospective cohort of women transitioning through menopause. We also considered multiple PFAS and assessed their joint effects on adipokine profiles. Given that leptin and adiponectin may account for the associations between adipose tissue and inflammation in individuals with overweight and obesity (Conroy et al., 2011), we conducted a secondary analysis with stratification by overweight and obesity status and hypothesized that women with overweight and obesity may be more vulnerable to the effects of PFAS on adipokines. To identify the time window of susceptibility during the menopausal transition, we also examined the associations between PFAS and adipokines stratified by menopausal status.
Section snippets
Study population
The present study included a sub-cohort of participants from SWAN, a multi-site, multi-racial/ethnic, community-based prospective study designed to characterize physiological and psychosocial changes that occur during menopausal transition (Santoro et al., 2011). In 1996 to 1997, a total of 3302 premenopausal women aged 42–52 years were recruited from seven study sites, including Boston, MA; Chicago, IL; Southeast MI; Los Angeles, CA; Newark, NJ; Oakland, CA; and Pittsburgh, PA. Each site
Participant characteristics
Table 1 shows participant characteristics and adipokine concentrations at SWAN-MPS baseline. Women had a median age of 49.5 (interquartile range, IQR: 47.3, 51.5) years. Nearly half of the sample (51.1%) was White, and 20.9% were African American, 12.6% Chinese, and 15.4% Japanese. Approximately half of women (51%) attended some college or more, and most (62.9%) were never smokers. Most women were pre- (11.4%), early peri- (50.7%), or late perimenopausal (8.4%), whereas only 14.8% were
Discussion
We found that leptin concentrations and FLI at a 3-year follow-up were significantly higher in women with higher baseline concentrations of PFOS, n-PFOA, PFNA, EtFOSAA and MeFOSAA. However, PFAS concentrations were not associated with sOB-R, total adiponectin, or HMW adiponectin. Thus, the association of PFAS with FLI is likely driven by the association of PFAS and leptin, not any differences in sOB-R. Further, the present study is the first to report the overall joint effects of PFAS mixtures
Declaration of competing interest
The authors declare no competing financial interest.
Acknowledgements
The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (Grants U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The study was supported by the SWAN Repository (U01AG017719).
This study was also supported by
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