When I started my lab at the University of California–Irvine (UCI) in 1998, I never imagined that I would work on endocrine disrupting chemicals (EDCs), obesity, or epigenetic transgenerational inheritance. However, as many successful scientists will tell you, one must follow the data where it leads, rather than trying to impose our own views on nature. My work on obesogens derives from a subtle evolution in my scientific interests that was grounded in a lifelong interest in how the embryo is patterned from the fertilized egg to a complex organism. As a postdoctoral fellow working on frog development at UCLA, I became interested in how small molecules might affect embryonic patterning and was greatly attracted to the work that Ron Evans’s laboratory at the Salk Institute was doing on nuclear hormone receptors. When Ron “scooped” us on identifying the nuclear retinoid X receptor (RXR), I decided to join his lab after a little persuasion by Davo Mangelsdorf and Kaz Umesono, the two senior researchers in Ron’s lab whom I had become friendly with. Ron created a very stimulating intellectual environment in his laboratory that has enabled him and his colleagues to make many, many seminal discoveries over the years. I joined Ron’s lab to start seriously searching for new hormones that could activate so-called orphan nuclear receptors, receptor-like molecules for which we did not know the corresponding hormone. Ron generously let me do pretty much whatever I wanted and never complained when my interests drifted away from his. Dr. David Gardiner at UCI first got me interested in studying chemicals in the environment that could activate the retinoic acid receptor as potential causal agents for the epidemic of deformed frogs that first appeared in Minnesota. I was already identifying new ligands for retinoic acid receptors in Ron’s lab so it was an easy jump to make. You can read about this story in Bill Souder’s excellent book, A Plague of Frogs.254 Ron did not bat an eye when I started spending a lot of effort on this project to the exclusion of what I was supposed to be working on (or when a Nightline news crew showed up to interview me in Ron’s lab without asking to talk with him). Although I did not realize it initially, a natural intersection of developmental biology and identifying new hormone receptor ligands is the field of endocrine disruption. I remember that Ron and I were sitting together at a Keystone endocrine disruptor meeting in 1999 when he leaned over to me and said, “You could probably make a big impact in this field if you wanted to.” The seed was sown.
Dave and I received a grant from the EPA to study deformed frogs after I joined the faculty at UCI and came tantalizingly close to identifying the environmental retinoid that might be responsible for the deformed frog problem. Unfortunately, the analytical methods available at the time were not up to the task and then the money ran out. But at the same time, the study of endocrine disruption was growing, particularly in Japan, and Professor Taisen (Tai) Iguchi (whom I had met at the same Keystone meeting mentioned above) invited me to an international endocrine disruptor meeting in Kobe, Japan. It was in Japan that my interest in endocrine disruptors was nurtured by the continuing interest shown by Tai and Professors Jun Kanno, Tohru Inoue, Masami Muramatsu, Satoshi Inoue, Yoshi Nagahama, and others. Their many invitations to speak about our work in Japan kept me abreast on what was happening in the field and convinced me to keep working in this area before our exciting discovery of obesogens. It was in Japan that I first met Professor Howard Bern, from UC Berkeley, who had a great influence on my career. Howard believed that the measure of one’s scientific career is not in what we discovered, but in “who we left behind,” that is, the achievements of the people we trained. This had a profound impact on my thinking. I “adopted” Howard as my wise grandfather since I never knew either of my actual grandfathers.
Professors John McLachlan from Tulane University and Lou Guillette from the University of Florida were also major influences on my developing interest in endocrine disruptors and as role models. Working together with the global community of endocrine disruptor researchers has been a major highlight of my scientific career. It gives me great pleasure and satisfaction that the work we do has direct impact on human health. Rather than the sometimes cutthroat competition that I faced in other fields, the endocrine disruptor community was welcoming and supportive, and readily accommodated new ideas and approaches. In addition to those I have already mentioned, colleagues and collaborators I wish to thank for their friendship, collaboration, and inspiration over the years include Tom Zoeller, Fred vom Saal, Laura Vandenberg, Chiharu Tohyama, Ana Soto, Toshi Shioda, Pete Myers, Lars and Monica Lind, Juliette Legler, Jerry Heindel, Andrea Gore, David Crews, and Andrés Carrasco. I thank Drs. Mike Skinner and John McCarrey for many stimulating discussions about epigenetic inheritance, most of which took place over Tusker beers on safaris in Kenya. Many thanks also to my green chemistry colleagues, Terry Collins and John Warner, who have totally changed how I think about chemical synthesis and design. Terry and John are truly changing the world. I hope that anyone I may have missed can forgive my leaky memory. Sadly Howard, Lou, and Andrés are no longer with us, but their influence on those of us who knew them is eternal.
The obesogen story has been a wild ride from its initial nearly absolute dismissal by the biomedical research community to the now growing acceptance that chemical effects on the genome and epigenome contribute to many chronic diseases, including obesity. Tai deserves the credit (or blame) for my interest in tributyltin (TBT) since it was through a collaboration with him that my laboratory first began to test this chemical, and it was at a meeting in Matsuyama, Japan, to which Tai invited me, where I first heard about the effects of TBT on vertebrates. I thank the NIEHS for its continuing financial support of the research in my laboratory, as well as the EPA and the greatly missed California Toxic Substances Research and Training Program, which was the first organization to find this work worthy of financial support.
Many people in my laboratory have worked on aspects of this project over the years. Dr. Raquel Chamorro-García has spearheaded all of the tedious and time-consuming transgenerational studies that are revolutionizing what we know about the effects of EDCs on physiology and the epigenome. Dr. Carlos Díaz-Castillo and my genomic collaborator Dr. Toshi Shioda from Massachusetts General Hospital have played important roles in helping to unravel what is happening to the epigenome as a result of ancestral TBT exposure. Soon-to-be Dr. Bassem Shoucri made major advances in figuring out just how EDCs affect the commitment of mesenchymal stem cells to the fat lineage through RXR, probably as a dimeric complex containing both RXR and PPARγ. Dr. Séverine Kirchner first found that TBT caused effects on the epigenome that altered the fate of mesenchymal stem cells. Séverine, Dr. Jasmine Li, and graduate student John Ycaza showed that the ability of TBT to change mesenchymal stem cells into fat cells required action of the nuclear receptor, PPARγ. Dr. Felix Grün was the first person in my lab to work on TBT and it was during a conversation about what to call the effects of chemicals like TBT on cells and animals that we coined the term “obesogen.” Many undergraduate students, graduate students, visiting scientists, and technicians contributed to this project over the years, including Rachelle Abbey, Tim Abreo, Sathya Balachander, Christie Boulos, Connie Chow, Giorgio Dimastrogiovanni, Heidi Käch, Tiffany Kieu, Jhyme Laude, Ron Leavitt, Lauren Maeda, Eric Martinez, Nina Ngyuen, Hang Pham, Nhieu Pham, Margaret Sahu, Weiyi Tang, Camilla Taxvig, Lenka Vanek, and Zamaneh Zamanian. A very special thanks is due to Dr. Amanda Janesick who as a graduate student in my laboratory undertook the writing of many reviews about the effects of obesogens with me, despite that this was not the topic of her thesis research. Amanda and I spent thousands of hours discussing and debating obesity and obesogens together and with other endocrine disruptor researchers around the world. Amanda’s irrepressible enthusiasm as a writing partner made working on these many reviews enjoyable and they ultimately served as the backbone of this book.
The genesis of this book was much faster. In January 2013, I received a call from the New York Times columnist Nicholas Kristof who had decided to write a story about obesogens. After a pleasant conversation and a few e-mails, Nick wrote an article that appeared in the Sunday Review on January 19, 2013, entitled “Warnings from a Flabby Mouse.”255 Many thanks to Nick for his interest and for writing the excellent article that started the chain of events culminating in this book. His article attracted the attention of several literary agents who later contacted me. Bonnie Solow, who is now my amazing agent, gently persuaded me that it was time to write a book about obesogens and that I was the one to write it. After many phone calls with Bonnie, I agreed, but spent the next two years proving convincingly that I could not find the time necessary to write the required book proposal. Undaunted, Bonnie connected me with collaborator Kristin Loberg. Kristin and I clicked immediately, worked marvelously together, and became fast friends. She did a masterful job of converting our many conversations and my published papers, talks, and random musings into the skeleton of this book. Throughout countless drafts bounced back and forth between us, Kristin helped me strike a good balance between being too technical and too trivial. Together we produced something I think is much better than what either of us could have done alone. Kudos also to Karen Murgolo and her staff at Grand Central Life & Style who have helped immensely in the evolution of this book. I have used the cartoons of Eric Jay Decetis and Geoff Olson to good effect in my talks for years and am thankful to both for permission to include these cartoons in this book. Thanks also to Jim Janesick for his illustration of the somatotypes and to Retha Newbold for the photograph of her flabby mice that started the field. I am also grateful to Tom Zoeller for agreeing to let me use his provocative quotes and anecdotes. Dr. Jerry Heindel read every word of the book and offered many helpful suggestions. Dr. Peter Turnbaugh provided detailed commentary on the microbiome section. Any errors and omissions remaining in the book are entirely mine.
I want to specially acknowledge Dr. Jerry Heindel whose optimism and encouragement helped get me through a very difficult time at the dawn of obesogen research. As the NIH program officer assigned to my TBT grants, Jerry was responsible for explaining to me why the study sections that reviewed my grants didn’t think they were worth funding. I remember he once said to me, “Listen, I don’t have any funds to give you, but I think that this work is really, really important and I hope you don’t give up, no matter how bad these reviews seem. I am sure there is something here and you are the one to find it.” I was a newly minted associate professor at that time just starting to work on a controversial new topic. This strong encouragement from an NIH official helped to keep my enthusiasm high until we finally had so much data in support of our model that the grant was funded. Jerry has become a good friend over the years and we have also spent countless hours discussing obesogens, metabolism, and endocrine disrupters. Jerry was a great travel partner and didn’t mind that my fast driving made him carsick. He is always up for talking science over a beer or two and his insights and honesty (occasionally brutal) have helped to hone my ideas and approaches.
Last, but not least, I thank my wife, Dejoie, and my daughter, Arielle, for their constant support and not complaining about my frequent absences over the years. I was fortunate to be invited to speak about our endocrine disruptor and obesogen research around the world and to occasionally take them with me to exotic new destinations. I was even luckier still that they entertained each other while I was abroad or when I abandoned them to attend scientific meetings in a strange city where they didn’t speak the local language. Arielle was blessed to grow up with a large extended family of scientific “aunts and uncles” who doted on her even more than we did. You know who you are.
This book grew from work in my laboratory performed between 2003 and 2017, together with the work of colleagues in the field of endocrine disruption and in other disciplines. It reflects the evolution of my thinking and that in related fields over the same time period. The idea that chemicals might cause or contribute to obesity was very “counter-culture” when we started so the narrative needed to be built from scratch. It was my original intent to write a book focused on the chemical obesogens that my lab studies, but it became clear during the writing that a different type of story was needed—a modern explanation of why and how we become fat, despite trying hard not to. I have tried to incorporate the most up-to-date evidence from all of the fields that we currently know may be related to obesity and to present the most complete and accessible story possible in the hope that it may help you to gain control of your weight and health. I hope that you enjoy the ride.