The role of polycarbonate monomer bisphenol-A in insulin resistance

Abstract

Bisphenol A (BPA) is a synthetic unit of polycarbonate polymers and epoxy resins, the types of plastics that could be found in essentially every human population and incorporated into almost every aspect of the modern human society. BPA polymers appear in a wide range of products, from liquid storages (plastic bottles, can and glass linings, water pipes and tanks) and food storages (plastics wraps and containers), to medical and dental devices. BPA polymers could be hydrolyzed spontaneously or in a photo- or temperature-catalyzed process, providing widespread environmental distribution and chronic exposure to the BPA monomer in contemporary human populations. Bisphenol A is also a xenoestrogen, an endocrine-disrupting chemical (EDC) that interferes with the endocrine system mimicking the effects of an estrogen and could potentially keep our endocrine system in a constant perturbation that parallels endocrine disruption arising during pregnancy, such as insulin resistance (IR). Gestational insulin resistance represents a natural biological phenomenon of higher insulin resistance in peripheral tissues of the pregnant females, when nutrients are increasingly being directed to the embryo instead of being stored in peripheral tissues. Gestational diabetes mellitus may appear in healthy non-diabetic females, due to gestational insulin resistance that leads to increased blood sugar levels and hyperinsulinemia (increased insulin production from the pancreatic beta cells). The hypothesis states that unnoticed and constant exposure to this environmental chemical might potentially lead to the formation of chronic low-level endocrine disruptive state that resembles gestational insulin resistance, which might contribute to the development of diabetes. The increasing body of evidence supports the major premises of this hypothesis, as exemplified by the numerous publications examining the association of BPA and insulin resistance, both epidemiological and mechanistic. However, to what extent BPA might contribute to the development of diabetes in the modern societies still remains unknown. In this review, I discuss the chemical properties of BPA and the sources of BPA contamination found in the environment and in human tissues. I provide an overview of mechanisms for the proposed role of bisphenol A in insulin resistance and diabetes, as well as other related diseases, such as cardiovascular diseases. I describe the transmission of BPA effects to the offspring and postulate that gender related differences might originate from differences in liver enzyme levels, such as UDP-glucuronosyltransferase, which is involved in BPA processing and its elimination from the organism. I discuss the molecular mechanisms of BPA action through nuclear and membrane-bound ER receptors, non-monotonic dose response, epigenetic modifications of the DNA and propose that chronic exposure to weak binders, such as BPA, may mimic the effects of strong binders, such as estrogens.

Keywords: BPA; Bisphenol-A; Diabetes; Endocrine disrupting chemicals; Epigenetic modifications; Insulin resistance; Non-monotonic dose response; Polycarbonate polymers.

Figure 1. The model of BPA effect on insulin resistance and diabetes.

Global model of the contribution of endocrine-disrupting chemical BPA to the development of insulin resistance and diabetes in humans. Light and temperature might induce the hydrolysis of polycarbonate plastics and subsequent leaching of BPA into the water and food sources. Once in human tissues BPA exerts its effects through ER receptors alpha, beta and gamma and estrogen mediated gene expression. In addition to the nuclear receptors, BPA can exert its effects through non-genomic, membrane associated receptors. Model indicates that BPA induced endocrine disruption may partially contribute to the development of insulin resistance, with major contributors being modern human diet and genomic composition. ER, estrogen receptor. ERR, estrogen-related receptor; GPER, G-protein-coupled estrogen receptor.

Figure 2. The prediction of non-monotonic dose response to BPA.

BPA may induce non-monotonic dose response as manifested by the appearance of the inverted U-shape curve, e.g., when insulin content is measured in isolated pancreatic islets after treatment with increasing concentrations of BPA (0.1–1,000 nM) for 48 h (Alonso-Magdalena et al., 2008). Computational modeling that takes into account the dimerization kinetics of the estrogen receptors and binding to either endogenous or exogenous ligand, or both (heterodimerization) accurately predicts the appearance of non-monotonic dose responses (both the U-shape and inverted U-shape curves). U-shaped dose response appears in case of the heterodimer L_enER-ERL_ex (also named LXXR) acting as a pure or partial activator, regardless of the nature of exogenous ligand. Non-monotonic inverted U-shape curve appears when exogenous ligand is an agonist, regardless of the activity of the heterodimer. Finally, monotonic response can also arise in two cases. L_en, endogenous ligand; L_ex, exogenous ligand.

Figure 3. Effective transmission of BPA effects to male offspring in mice.

Acute BPA treatment during gestation leads to severe glucose intolerance, decreased insulin production, and altered glucose metabolism that is being transferred to the male offspring. During the early life in male offspring there is a surplus in insulin signaling and insulin production that ultimately leads to decreased pancreatic beta mass and glucose intolerance in adulthood. Female offspring is protected from the BPA effects due to the higher levels of the enzyme involved in BPA glucuronidation process and elimination of BPA from the organism.

Figure 4. BPA induced epigenetic modifications are actively transmitted to offspring.

BPA can induce changes in DNA methylation in the placental tissue, as well as in the embryo of the F1 generation. Modifications in DNA methylation at the DMR—differentially methylated regions induce changes in gene expression and LOI—loss of imprinting (loss of monoallelic expression) of at least three imprinted genes (Snrpn, Igf2 and Kcnq1ot1). In the case of Igf2 increased methylation leads to the loss of expression of the neighboring H19 gene from the maternal allele and subsequent biallelic expression of Igf2. In the case of Snrpn and Kcnq1ot1 the loss of methylation at the DMR leads to biallelic expression of these genes. In the liver in F1 and F2 generations, DNA methylation of the Gck (glucokinase) gene promoter decreases its expression. In F1 generation Gck contains hypermethylated one CpG island (out of 5 CpG islands in total present in the promoter of the Gck gene). In F2 generation, DNA methylation is increased as all 5 CpG islands become methylated.

Figure 5. Maximal biological effect of BPA is confined to a narrow range and dependent on dose, gender and developmental stage.

BPA exerts effects that follow non-monotonic dose response (e.g., the inverted U-shape curve), therefore a narrow concentration window might exist that is essential for the BPA action. Concordantly, BPA will show its maximal effect in the narrow window of developmental stages (e.g., P6–PND0). These confined ranges of maximal BPA effects, together with the gender related differences, comprise a specific set of conditions for the maximal biological and physiological effect of BPA.