The discovery of plasticizers and their myriad uses has revolutionized our society. These compounds have created an age of convenient single-use products, improved medical devices, and advanced consumer products. We come into contact with plastics and plasticizers on almost a daily basis, and as a result, they are some of the most highly produced chemical entities in the world. Bisphenol A (BPA) is one such plasticizer, whose utility and chemical properties have made it highly amenable to consumer product use. As a result, millions of tons of BPA are produced each year, which has led to widespread human exposure through the air, water, soil, and consumer products.

The endocrine-disrupting properties of BPA were discovered early on, given its phenolic nature and similarity to steroid structures. However, its use since its discovery in the 1940s has only continued to grow. Concern about BPA and other plasticizers reached the mainstream media in the early 2000s, prompting regulatory reviews of its use in consumer products and, in particular, its use in infant products. In 2007, US regulatory agencies evaluated BPA toxicology data. They determined that nanomolar levels of BPA exposure was safe for adults but noted “some concern” about the effects of BPA on fetuses, infants, and children.¹  Since this decision, hundreds of scientific studies have been published that continue to question the safety of BPA. Critically, there is a significant weight of evidence that BPA exposures in the 10–100 nM range have adverse outcomes, which include inducing reproductive toxicity, altering metabolism, affecting neurobehaviors, and sensitizing tissues to carcinogenic challenges.^2–7  The carcinogenic potential of BPA has been a growing focus area with epidemiological studies linking BPA exposures with breast and liver cancer development^8–12  and neoplastic changes in other reproductive organs and tissues.⁵  Despite this weight of evidence, the health risks associated with the chronic nanomolar BPA exposure experienced by the population are still controversial due to a lack of molecular mechanisms describing the pleiotropic effects of observed exposures.^13–17  The pleiotropic effects induced by BPA have made understanding its modes of action and characterizing the consequences of exposure challenging.

I first began studying BPA in 2012 under the guidance of Dr Samuel H. Wilson at the National Institute of Environmental Health Sciences. We were interested in the induction of DNA damage by BPA and its impact on DNA repair mechanisms. Our studies found that BPA induces DNA damage directly and indirectly through reactive oxygen species.^18,19  More importantly, we also found that BPA exposure alters DNA damage response and repair mechanisms, promoting the persistence of mutagenic DNA lesions within the genome.^18,19  These findings were especially interesting, because they occurred in cell-line models that lacked or have extremely low expression of estrogen receptors. Thus, we identified a critical role for the metabolism of BPA and its generation of reactive species in promoting adverse cellular consequences.²⁰ 

Our work and that of numerous others have begun to identify modes of action for BPA that are not linked to the classical estrogen receptors. BPA's modes of action have been found to use other steroid receptors, non-classical estrogen receptors, and even direct interactions with signaling molecules like RAS.²¹  It is becoming increasingly appreciated that BPA has multi-modal effects. In addition to non-monotonic dose responses, these effects have likely confounded our ability to understand the cellular and organismal consequences of BPA exposure.

While there are significant efforts across the globe to better understand our exposure to BPA and other endocrine-disrupting chemicals, the health risks associated with the chronic BPA exposure experienced by the human population are still unknown. The lack of molecular mechanisms describing the pleiotropic effects observed with BPA exposures significantly contributes to this problem and needs to be addressed by funding and regulatory agencies.^13–17  When I embarked on my first study of BPA, I did not understand the impact it would have on my research and worldview. BPA is a persistent environmental toxicant from which we will continue to experience exposure effects for decades to come. Its reproductive toxicity means our children and grandchildren will experience these effects as well. There is a wide global effort underway to understand these effects. In this book, we highlight the multi-modal mechanism of BPA and examine its cell and organismal consequences. As noted in most chapters in this volume, much more work is needed to understand better the impact of BPA on the genome, epigenome, and proteome. However, as the work highlighted in this volume shows, we have made progress in understanding BPA's multi-modal effects. The global research efforts highlighted here also demonstrate that we will continue to progress, and hopefully, eventually alleviate the impact that BPA and other endocrine-disrupting chemicals have on our population.

Natalie R. Gassman