Bisphenols Come in Different Flavors: Is "S" Better Than "A"?

In this issue, Boucher et al (1) describe the stimulatory effects of bisphenol S (BPS) on the differentiation and lipid accumulation in human adipocytes. Human exposure to bisphenol A (BPA), and very recently to its close analog BPS, has been associated with widespread health concerns for over 2 decades. Consequently, this subject deserves a brief perspective with respect to the following: 1) the prevalence of the bisphenols in the environment and the extent of human exposure; 2) their metabolic activities and putative mechanisms of action; and 3) an overview of ongoing conflicts between research scientists, environmental groups, the chemical industry, and regulatory agencies in the battle over the recognition of bisphenols as hazardous endocrine-disrupting chemicals (EDCs). BPA is a synthetic small molecule composed of 2 phenol groups. It is produced in very large quantities (over 5.4 million tons worldwide in 2015) in the manufacture of polycarbonate plastics and epoxy resins, both of which are made of repeating BPA monomers (Figure 1). BPS is an analog of BPA with a similar structure of 2 phenol groups on each side of a sulfonyl group (2). Polymers made of repeating BPS units are called polyethersulfone (PES). BPA-containing consumer products include plastic bottles, food utensils, lining of beverage and food cans, as well as dental cements, thermal receipt papers, iv medical devices, and water pipes (3). Although the carbonate linkages are rather stable and the polymers are chemically inert, BPA can leach out as a result of incomplete polymerization and/or because of some degradation of the polymer by elevated temperatures or acidic conditions (4, 5). Humans can be exposed to BPA through ingestion, skin absorption, inhalation, and through iv catheters. BPA at nanomolar concentrations has been measured in blood or urine of most individuals tested and has also been detected in the amniotic fluid and fetal plasma, indicating its passage across the placental during pregnancy, and underlying its potential to affect human fetal development (6). Given the worldwide use of polycarbonate plastics, epidemiological studies have had difficult times finding control groups that have not been exposed to BPA. BPA was first synthesized in 1891, with the first evidence for its estrogenicity coming from studies with ovariectomized rats in the 1930s. A landmark study in 1993 found an estrogen-like compound in water autoclaved in polycarbonate bottles for use in tissue culture, which was subsequently identified as BPA (7). Although BPA-based plastics have been in commercial use since the 1950s, reports on its estrogen-like properties with an environmental impact began to appear only in the early 1990s (8). Figure 2 shows an exponential increase in publications on BPA in PubMed, reaching 3000 between 2011 and 2015 and totaling over 6000. In response to the increasing pressure by concerned scientists and environmental groups to ban the use of BPA in consumer products, the chemical industry began to introduce BPS as a “safe substitute” for BPA in the mid2000s. Structural/chemical data show that PESs have excellent thermal, optical, and mechanical properties as plastics. However, soon thereafter, reports on EDC properties of BPS began to appear (Figure 2) (2), as well as initial findings on its detection in human urine (9). By now, thousands of in vitro and in vivo studies have provided evidence that BPA is a prototypical EDC that affects reproduction, neural development, behavior, cardiovascular functions, and metabolism, as well as the promotion of several types of cancer. Extensive research has revealed that there is no single mechanism by which BPA acts as an estrogen agonist. Proposed targets include clas-