Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes

Abstract

Background: The incidence of obesity has risen dramatically over the last few decades. This epidemic may be affected by exposure to xenobiotic chemicals. Bisphenol A (BPA), an endocrine disruptor, is detectable at nanomolar levels in human serum worldwide. Adiponectin is an adipocyte-specific hormone that increases insulin sensitivity and reduces tissue inflammation. Thus, any factor that suppresses adiponectin release could lead to insulin resistance and increased susceptibility to obesity-associated diseases.

Objectives: In this study we aimed to compare a) the effects of low doses of BPA and estradiol (E(2)) on adiponectin secretion from human breast, subcutaneous, and visceral adipose explants and mature adipocytes, and b) expression of putative estrogen and estrogen-related receptors (ERRs) in these tissues.

Methods: We determined adiponectin levels in conditioned media from adipose explants or adipocytes by enzyme-linked immunosorbant assay. We determined expression of estrogen receptors (ERs) alpha and beta, G-protein-coupled receptor 30 (GPR30), and ERRs alpha, beta, and gamma by quantitative real-time polymerase chain reaction.

Results: BPA at 0.1 and 1 nM doses suppressed adiponectin release from all adipose depots examined. Despite substantial variability among patients, BPA was as effective, and often more effective, than equimolar concentrations of E(2). Adipose tissue expresses similar mRNA levels of ERalpha, ERbeta, and ERRgamma, and 20- to 30-fold lower levels of GPR30, ERRalpha, and ERRbeta.

Conclusions: BPA at environmentally relevant doses inhibits the release of a key adipokine that protects humans from metabolic syndrome. The mechanism by which BPA suppresses adiponectin and the receptors involved remains to be determined.

Keywords: adipocytes; adiponectin; bisphenol A; estradiol; estrogen receptors; estrogen-related receptors; human adipose explants; obesity.

Figure 1

Suppression of adiponectin release from breast adipose explants by BPA, E₂, and ICI. (A) Typical dose response by explants from one patient; each value is the mean ± SE of six determinations. (B–D) Responses of explants from eight women to 1 nM BPA (B), E₂ (C), or ICI (D), illustrating variation among patients in both basal adiponectin secretion (see also Table 2) and responsiveness to the test compounds. ^*p < 0.05 compared with control.

Figure 2

Suppression of adiponectin release from abdominal SC adipose explants by BPA, E₂, and ICI. (A) Typical dose response by explants from one patient; each value is the mean ± SE of six determinations. (B–D) Responses of explants from nine women to 1 nM BPA (B), E₂ (C), or ICI (D), illustrating variation among patients in both adiponectin secretion and responsiveness to the test compounds. ^*p < 0.05 compared with control.

Figure 3

BPA and E₂ suppress adiponectin release from mature abdominal SC adipocytes from a non-obese woman (A) and an obese woman (B). (A) Effect of treatment with increasing doses of BPA or E₂. (B) Effect of treatment with increasing doses of BPA, E₂, and ICI. Each value is the mean ± SE of four determinations. ^*p < 0.05 compared with control.

Figure 4

Effects of BPA, E₂, or ICI on adiponectin release. (A) Time-dependent effect of 1 nM BPA or E₂ on adiponectin release from SC and VIS (omental) adipose tissue explants from a morbidly obese woman. (B) Effect of treatment with increasing doses of BPA and E₂, as well as 1 nM ICI, on adiponectin release from matched abdominal SC and VIS (omental) adipose tissue explants from a morbidly obese man. Each value is the mean ± SE of six determinations. ^*p < 0.05 compared with control.

Figure 5

Depot-specific differences in the expression of putative receptors that may mediate the action of BPA or E₂, as determined by real-time reverse transcriptase PCR. (A) Differences in expression of ERα, ERβ, GPR30, ERRα, ERRβ, and ERRγ in SC and breast (BR) adipose tissue calculated as fold change (shown above bars) relative to VIS adipose tissue. (B) Relative abundance of the above receptors in VIS adipose tissue compared with ERαexpression.