We can now prove that environmental influences will trump genetics when it comes to making us fat as a result of the effects that obesogens have on physiology and, especially, fat metabolism. Obesogens can create permanent glitches in a system that is otherwise expertly regulated. Obesogen exposure programs the body to store more of the calories you consume as fat and mobilize less of your stored fat for burning.⁷⁷ In this chapter, I will complete the story with the details of exactly how this happens. Since my laboratory introduced the concept of obesogens to the scientific community with the discovery that tributyltin exposure makes mice fat, numerous other chemicals have been identified as obesogens or potential obesogens. For the record, I define a bona fide obesogen as a chemical known to increase weight in a living organism, whereas a potential obesogen can induce cultured cells (grown in a laboratory dish) to become fat cells or control gene expression pathways known to promote the development of fat cells and obesity.

Let’s get up close and personal with how obesogens work in the body, the way they reprogram cell fates and adversely change physiology, and how their effects can be passed on to future generations. There are quite a few known obesogens that can act both directly and indirectly through a variety of mechanisms.

I will be discussing some basic biology and endocrinology, subjects that are key to understanding obesogens in their complexity. You will soon know much more about how people get fat in the twenty-first century and what must be done to combat it.

HORMONE HAVOC: ENDOCRINE DISRUPTING CHEMICALS

Many obesogens belong to a larger family of troublesome compounds called endocrine disrupting chemicals, introduced earlier. So let’s go there first. The field of endocrine disruption is historically rooted in reproductive endocrinology and wildlife biology. The idea that synthetic chemicals could change hormonal systems to cause adverse effects in wildlife and humans was first proposed in 1991 at the watershed Wingspread Conference held in Racine, Wisconsin, organized by Theo Colborn. In 1996, Theo and Pete Myers sounded the alarm and conveyed these concepts to the public in their book, Our Stolen Future.⁷⁸ In a nutshell, Theo and Pete identified particular negative effects in animal populations from a number of studies around the world that could be explained by inappropriate changes to their endocrine systems caused by chemical exposure. In my world, EDCs are defined as chemicals that come from outside the body (including pharmaceuticals), or mixtures of such chemicals, that interfere with any aspect of hormone action.⁷⁹ EDCs mimic or interfere with the actions of natural hormones produced in our bodies, leading to disrupted physiology and a variety of harmful effects. This definition differs from that used by the U.S. Environmental Protection Agency (EPA) and the toxicology community, who would add, “And cause adverse effects in living organisms.”⁸⁰ To an endocrinologist, disruption of hormone action is adverse in itself. We will talk more about EDCs and how we are exposed later in the book. For now, suffice it to say that EDCs are ubiquitous and we are exposed to them in many, if not most, man-made products we encounter in our daily lives.

A very important concept to grasp when it comes to the actions of hormones and how they impact physiology is that the same hormone at the same amount will have different effects on adults from those it will have on developing embryos, fetuses, or children. “Activational” effects are rapid, temporary effects that come and go with the presence and absence of the hormone. “Organizational” effects, on the other hand, are permanent because these change the structure and function of an organism in a way that cannot be reversed. Let’s explore these two types of effects with examples and then bring them into context with EDCs.

Activational types of hormone action are important for physiological homeostasis—the process by which the body stays balanced. The hormone-receptor complex functions much like a thermostat. When hormones are present and bind to their receptors, physiological processes are triggered until the hormone is removed (or when the temperature is lower than the set point, the thermostat turns on the heat until the set temperature is reached, then it turns the heater off). Many hormones induce the expression of inhibitors of their own action so that we are not subject to runaway signaling, as if the thermostat were broken and the heater or air conditioner continued to run without stopping. When you are suddenly threatened, for example, adrenaline will rush through your body creating the prototypical “fight or flight” response to the perceived stress. When the threat passes, hormone levels wane and your body returns to normal. This is essential for overall homeostasis in the body. When all hormones and related molecules are balanced, the body works as it should: organs function properly, and your metabolism operates smoothly. Conversely, prolonged, significant variations in hormone levels can wreak havoc on bodily functions, especially those that control metabolism.

In contrast to activational effects, hormones can also act during fetal development and throughout early life and puberty until adult maturity. These “organizational” effects of hormone action permanently alter the organization, proliferation, differentiation, and size of cells, tissues, and organs. My colleague R. Thomas (Tom) Zoeller from the University of Massachusetts uses a vivid analogy to illustrate the difference between activational and organizational effects. If you expose an adult woman to sufficient levels of anabolic steroids such as testosterone, she will grow bigger muscles and more body hair, both of which will eventually disappear after the hormone is removed—this is activational. On the other hand, if you expose a female fetus to high doses of testosterone, her clitoris will instead develop into a penis. This penis will not turn back into a clitoris when the testosterone is removed—it is there permanently, an organizational effect. Organizational effects of hormone action explain how early life exposure to EDCs can lead to permanent effects on the exposed individuals. For example, they are the reason a baby’s exposure to pesticides can permanently change his or her body—from altering metabolism to increasing the risk for cancers and other diseases—for life.

Rachel Carson first made the connection between synthetic chemicals and cancer in her classic book, Silent Spring.⁸¹ By the time the Wingspread Conference was held almost thirty years later, it was widely understood that several pesticides were linked with cancers. Theo Colborn had a different and more expansive view. As a wildlife biologist, she noticed that top predators (birds, fish, mammals) in the Great Lakes region had a variety of reproductive defects that were also observed in their offspring. She worried that the ability of these species to reproduce was being compromised by their chemical exposures. While cancer is definitely frightening to most of us, impairing the ability of a species to reproduce is the surest way to cause its extinction—a far scarier prospect, I think.

Some of the most widely studied EDCs are chemicals that alter the balance of sex hormones in wildlife and contribute to adverse reproductive outcomes such as sex reversal and/or sterility in aquatic animals, including fish and marine animals. EDCs were first identified as substances that interfere with the action of estrogens, androgens, and thyroid hormone. These are in fact the primary focus of the Endocrine Disruptor Screening Program, run by the EPA, which was intended to test chemicals for their potential to adversely change hormonal signaling and protect the public from the harmful effects of endocrine disruptors. We know now that EDCs can alter hormonal signaling systems by tinkering with many more receptors than just these three hormones. In principle, any of the many types of hormone receptors previously discussed can be inappropriately regulated by EDCs.

But how do EDCs disrupt hormonal function? One obvious way is for them to mimic naturally occurring hormones in the body, as DDT does with estradiol (the major estrogen in human females). DDT is a pesticide that was used widely in the United States before it was banned in the 1970s because it adversely affected wild bird populations and could potentially harm human health; today it is among the most well-known EDCs. Another way would be for EDCs to block activation of hormone receptors so that the natural hormone no longer works, as the major breakdown product of DDT, called DDE, does with the androgen (testosterone) receptor. EDCs can make cells more sensitive to stimulation by existing hormones or disturb normal hormone levels by inhibiting or stimulating the production and metabolism of hormones or by changing the way hormones are transported to target tissues.

Contrary to what the chemical industry wants us to believe, the effects of EDCs, just like those of hormones, can occur at very low levels. This is a key point, because you will often hear that “the dose makes the poison” and that the doses of EDCs and other toxic chemicals to which we are exposed are far too low to harm us or to stimulate hormonal pathways in our body. Some industry apologists suggest that EDCs probably don’t even get into our bodies when we are exposed to them as intended by the manufacturers.

If you are leaning toward believing this argument, I recommend that you read a book by Rick Smith and Bruce Lourie called Slow Death by Rubber Duck.⁸² Smith and Lourie used themselves as experimental subjects and tested the hypothesis that no significant amounts of chemicals gets into our bodies from using products as intended. They established personal baselines by measuring concentrations of chemicals such as phthalates and PFOA in their blood. Next they did normal things such as spray an air freshener in a room or stain repellent on a couch, then sat in the room or on the couch and watched television. After a day or two they had their blood measured again and, surprise, surprise, significant levels of phthalates and PFOA were found. These are among the most ubiquitous of obesogens.

“The dose makes the poison” happens to be the central dogma of toxicology (the study of poisons). Traditional “dose makes the poison” toxicologists (that is, most government and industry toxicologists) assert that all substances (even water and air) are toxic and differ only in how poisonous they are (in other words, the amount it takes to kill you—their “potency”). This preposterous idea dates back to the so-called father of toxicology, the Swiss alchemist, astrologer, mystic, occultist, and physician Philippus Aureolus Theophrastus Bombastus von Hohenheim, more well-known as Paracelsus, who worked in the early 1500s. Paracelsus believed that poisons came from the stars and that “all things are poison, and nothing is without poison; only the dose permits something not to be poisonous.”⁸³ In this view, everything is a poison above some threshold dose, below which no adverse effects occur.

Although dose is certainly important, the argument that the dose makes the poison is patently wrong in many ways and on at least three counts with respect to EDCs.⁷⁹ First, the endocrine system in our bodies is already active. Therefore, rather than an EDC needing to activate a system that is “off” (and might require some threshold amount to turn on), the hormonal system in living organisms that use hormones is already “on” and can easily be disrupted by small amounts of EDCs. Second, since EDCs can have effects at very low doses (less than parts per billion), the entire concept of a “safe dose” below which we can comfortably believe there will be no harm is completely false. “Safe doses” for both acute or chronic exposures are often established by the EPA at much higher than parts per billion. Third, it is impossible to formally demonstrate the existence of a threshold for EDCs; moreover, even if you assumed that much of the population is “safe” from the doses we experience, you can bet that there will be some segment of the population that is sensitive to the doses they experience. Each one of us carries our own susceptibilities to chemicals. But government regulators largely test only for overt poisoning and completely miss the boat on long-term effects, particularly of EDC exposure.

There are more than eighty-four thousand chemicals registered with the EPA in commerce, most of which are poorly studied, and more than eight million unique chemicals available for purchase worldwide. Current studies have identified approximately one thousand of these chemicals that meet the criteria of an EDC. The actual number of EDCs is likely to be much larger because there has been no systematic effort under way anywhere to identify which of this deluge of synthetic chemicals are EDCs. As mentioned, these compounds are used in a wide range of consumer products, including food packaging, building materials, clothing and upholstery, personal care products, detergents and other cleaning agents, plastics, and medical equipment. They are also used as pesticides and in industrial processes, leading to unintended contamination of food, water, and air. This means that we can be exposed to EDCs through what we eat, breathe, and put on our skin. EDCs abound even in hospitals.

My point in bringing this up is not to give you a sense of hopelessness or doom but rather to emphasize that you are largely on your own with respect to protecting yourself from chemical exposure. Government risk assessors (officials who assess the potential risk of chemical exposure to health) are heavily influenced by the industries they regulate, and the situation will only become much worse as Trump-era appointees remove environmental laws and regulations one by one. As Tom Zoeller put it most eloquently, “Chemical risk assessment is a collaboration between government and industry to expose the public to toxic chemicals for profit.” It is precisely that—how much of a potentially useful toxic chemical (for example, a pesticide or herbicide) can be put into the environment before people start dropping dead in the streets? So far, risk assessors are doing a reasonably good job at that—people are not dying from chemical poisoning in the streets. Beyond this, you are on your own—there is little testing for and protection from chronic effects of chemical exposure at the levels we experience every day.

Another big problem with EDCs is that many are persistent and can bioaccumulate in our tissues, meaning their concentration increases over time. They also can become biomagnified; that is, their concentration increases at successive levels of consumption from plants to animals to humans. Perhaps you know about mercury contamination in seafood. Mercury ends up in the oceans as a result of coal-burning power plants, mining, and plastic production, among other sources. It is taken up by algae, which are eaten by small animals, which are eaten by small fish, which are eaten by larger fish, and so on. Eventually, the top predators such as swordfish, sharks, bluefin tuna, tilefish, and others accumulate mercury levels that can be dangerous to humans. While some EDCs, such as BPA, are not thought to accumulate in the body, many EDCs can be stored in fat cells for years after exposure and passed on to children during pregnancy or when breastfeeding (and no, you can’t do a cleanse or detox to remove them quickly). For this reason, in the late 1990s the World Health Organization (WHO) and United Nations Environment Programme (UNEP) adopted the Stockholm Convention on Persistent Organic Pollutants, which seeks to severely reduce the production and use of chemicals that do not degrade in the environment. Would you be surprised to learn that as of this moment, the U.S. Senate has not ratified this treaty, despite the fact that virtually every other country in the world has done so? Given the current political climate, it does not seem likely that we will ratify it anytime soon.

The chemical apologists have yet another argument in their arsenal that we hear frequently: no one has conclusively demonstrated endocrine disrupting effects in humans. The implication is that only controlled human trials such as those the U.S. Food and Drug Administration (FDA) requires to license drugs would provide persuasive evidence that a chemical causes harm to humans. Fortunately for people everywhere, it is unethical, immoral, and illegal to conduct such experiments on humans. Ironically, industry uses a selected subset of animal studies to support its claims that chemicals are safe, while demanding evidence from human studies, which would be illegal to perform, to refute these claims. This is a typical yet unsupportable double standard. In reality, only drug side effects, accidental human exposures, or occupational exposures can provide anything approaching cause-and-effect data for chemical exposure in humans.

Sadly, we have some examples. A pharmaceutical EDC called diethylstilbestrol (DES) was prescribed by obstetricians throughout the mid-twentieth century with the aim of helping women avoid pregnancy complications and miscarriage, despite evidence from animal studies that it caused cancer.⁸⁴ Regrettably, children born from DES-treated mothers (“DES sons” and “DES daughters,” as they came to be known) were found to be at higher risk for certain cancers, infertility, miscarriage, and ectopic pregnancies, all of which had been observed in the earlier animal studies. This is another example of an organizational effect, because the children exposed during pregnancy suffered the permanent effects, whereas the mothers were relatively unaffected.

Accidental poisoning events are tragic, but they stand as important proofs of the effects of EDCs on humans. An industrial mishap in 1968 Japan led to the production of cooking oil containing polychlorinated biphenyls (PCBs) and related chemicals. Consumption of this contaminated oil, and foods cooked with it, caused Yushō disease, as it was called, led to the death of almost half a million birds, and sickened more than fourteen thousand people. The human effects were cognitive impairment in children, defects in the immune system, and irregular menstrual cycles (all symptoms of endocrine disruption), together with many other negative outcomes. An almost identical incident and effects occurred in Taiwan ten years later, which confirms that PCB exposure was the cause. Perhaps not surprising, similar effects were observed in animal studies and in wildlife exposed to PCBs. You might expect that we as a society (and particularly government regulators) should be smart enough by now to heed such lessons and prevent the harm that EDCs cause before exposures occur. Unfortunately, this is not the case. On the bright side, part 2 of this book will tell you how to avoid exposure to obesogens and EDCs of all types.

HORMONAL CONTROL OF FAT DEVELOPMENT

At about the same time that reproductive biologists and wildlife biologists became aware of EDCs, fat tissue was only beginning to become accepted as a bona fide endocrine organ itself, let alone an organ whose function could be disrupted by environmental chemicals.

The identification of fat as an endocrine organ was largely instigated by the discovery of leptin, which is one of a group of hormones that control hunger and fat storage. Leptin reduces the urge to eat by acting on specific receptors found in areas of the brain such as the hypothalamus, which regulates appetite (among other things). Many obese people are insensitive to leptin, which prevents them from responding to normal satiety signals. They continue to consume calories even though sufficient energy has been stored already (more on this shortly).

Another important finding clueing us in to the role of hormones in fat development has been the discovery of the master regulator of fat cell development, a nuclear hormone receptor with a long, terrible name that is an artifact of history: peroxisome proliferator-activated receptor gamma (PPARγ). In fact, PPARγ is a fatty acid receptor. Activating PPARγ initiates a program of gene expression controlling numerous genes involved in fat cell production, fatty acid synthesis, and storage. You will be hearing a lot about PPARγ because we have shown that it is a major target for chemicals that alter fat metabolism for the worse.

In addition to recognizing that fat tissue is an extremely active endocrine organ, we know now that it is highly connected to steroid hormones (estrogens, androgens, and glucocorticoids, the latter of which are a group of hormones involved with metabolism and the stress response system) and that fat maintains a close relationship with the immune system. It is becoming clear that disruption of fat tissue function could contribute to diseases beyond obesity alone. Excess or dysfunctional fat tissue can, in fact, have a hand in the development of diabetes, infertility, and even cancer. To really get a sense of how obesogens impact the body, it helps to understand their relationship with fat tissue.

FAT PROGRAMMING

Take a look at the two mice here. They were raised in the same lab and given the same food and opportunity to exercise. The only difference between the two is that the mouse on the right was exposed to a tiny amount (5 parts per billion, the equivalent of about ten drops in an Olympic-sized swimming pool) of an obesogenic endocrine disrupting chemical (in this case, the synthetic estrogen diethylstilbestrol) for the first five days after birth. This brief exposure programmed the mouse to put on fat later—not until many months after the exposure stopped. Although there were no detected differences in caloric intake or energy expenditure throughout its life, it continued to fatten up.⁸⁵

The notion that chemical exposures can turn your body into a fat-storage (as opposed to a fat-burning) machine, reprogram cells to become fat cells, and predispose you to become fat on a normal diet is daunting to ponder. How can this happen? In our own work with tributyltin (TBT), we showed that in mice exposed to very low levels of TBT in utero, mesenchymal stem cells (MSCs) found in the bone marrow and white adipose tissue are predisposed to become fat cells in far greater numbers than MSCs isolated from mice that were not exposed to TBT. MSCs are precursor/regenerative cells in our bodies responsible for first producing and later maintaining a large number of tissues, including bone, cartilage, muscle, fat cells, and some types of neurons. A key point to understand is that the developmental switch between fat and bone lineages is mutually exclusive: either the MSCs become fat cells or they become bone cells. Therefore, TBT exposure leads to more fat cells and fewer bone cells over time.

What we know so far is that one way in which TBT can induce weight gain is through that master regulator of fat cell development I mentioned earlier, PPARγ. The amino acid sequence of the PPARγ protein changes very little between humans and other mammals, and even between humans and more distantly related vertebrates such as frogs. PPARγ may be particularly susceptible to EDCs because it has a large “pocket” for binding to molecules and can accommodate many chemical structures. When a molecule capable of activating PPARγ enters the pocket, it forces PPARγ to change its shape, which then attracts a host of other cellular proteins that together bind to PPARγ-responsive genes and increase their expression. Among these PPARγ-responsive genes are many that are essential for fat cell development and function.

TBT promotes fat cell development in at least two ways. First, it induces expression of PPARγ in MSCs, which commits them to become fat cells. Second, it then activates PPARγ to turn on the genetic program that controls fat cell differentiation. My lab has also shown that when our animals are exposed in utero to TBT, but then never again, the damage has already been done: TBT causes a permanent effect on the metabolism of exposed animals, predisposing them to make more and bigger fat cells and to gain weight over time despite a normal diet. This was a heretical idea that met with considerable opposition from the medical establishment in the early days but has since been confirmed by multiple labs around the world working with TBT in different animals and with other obesogens in rodents. TBT can cause increased fat storage in fish, rats, and frogs. A group in Finland has even shown that levels of TBT in the placenta of pregnant women are closely correlated with weight gain in those babies when they are three months old.⁸⁶ These children are now twenty years old, and it will be very interesting to learn what effects maternal TBT exposure has had on their body fat as young adults if the researchers secure the needed funding for a follow-up study.

My lab has also shown that exposure to other chemicals can lead to weight gain in mice,ⁱⁱ such as the fungicide triflumizole, which is widely used on green leafy vegetables (one important reason to buy organic fruits and vegetables whenever you can).⁸⁷ Other labs have shown that exposure to estrogenic chemicals (for example, diethylstilbestrol, bisphenol A, and the pesticide DDT), organophosphate, organochlorine and neonicotinoid pesticides, flame retardants, alkylphenols, and phthalates all lead multiple animal species to increase fat storage.⁷ Many of these are also linked with weight gain in human epidemiological studies. As we will see coming up, many of these chemicals are found in everyday products. You don’t need to memorize a long list of chemical names. I will show you later in the book how to effortlessly steer clear of them without searching for them on a label (if there is one).

Many more chemicals have been shown in the lab to cause MSCs or other types of cells to differentiate into fat cells. These include alkylphenols, phthalates, flame retardants, and the plastics component bisphenol A diglycidyl ether, which is commonly used as a building block of epoxy resins and found in the lining of food and beverage containers.²³^,⁸⁸ A large number of these are agrochemicals (mostly fungicides)⁸⁹ that are sprayed on grains, fruits, and vegetables during conventional farming, which further points to the health value of eating organic, as we will discuss in chapter 6. Turning cultured cells into fat cells does not prove that they will be obesogenic in humans or animals, but I do not know of a single chemical that caused cultured cells to become fat cells that did not also have the same effects when tested in animals.

TRANSGENERATIONAL EFFECTS OF EDCs AND OBESOGENS

One of the most startling findings about obesogens has been their power to be passed on to future generations. For example, Dr. Raquel Chamorro-García in my lab found that when she bred the offspring of TBT-exposed mice, the effects were inherited.⁹⁰ Raquel exposed pregnant mice to low levels of TBT (far below the levels at which adverse effects are observed in toxicological studies and comparable to allowable human exposures) in their drinking water throughout pregnancy. In genetic terminology we call these pregnant mice the F0 animals, and their offspring are labeled as the F1 group. The baby mice (pups) exposed while they were in utero got slightly fatter, had MSCs reprogrammed to make more fat cells, and also had fatty livers.

When Raquel bred these F1 mice to produce the next generation (F2), she found that they, too, showed the same effects, and this continued on for another two generations (F3 and F4).⁷⁷^,⁹⁰ Put in human terms, the exposed woman’s children (F1), grandchildren (F2), great-grandchildren (F3), and great-great-grandchildren (F4) were all affected in the same way by her exposure to TBT during pregnancy. Although you might logically reason that TBT caused a permanent genetic mutation in the F1 generation that was then passed down to future generations, you would be wrong. We used so many different litters of pregnant F0 mice that there is no possibility the same mutation was induced randomly in all of them. Something else happened, and we will discuss that next.

EPIGENETIC—NOT GENETIC—CHANGES

So why did we even think to look for effects of TBT in the offspring of the exposed animals? The short answer is Professor Michael Skinner, a prominent reproductive biologist in the School of Biological Sciences at Washington State University. In 2005, Mike’s group published a study that sent shock waves through biology that continue to reverberate today. Mike and his colleagues exposed pregnant rats to relatively high levels of a commonly used fungicide called vinclozolin (that happens to antagonize testosterone and is widely used on wine grapes, fruits and vegetables, and golf courses) or a pesticide called methoxychlor (that mimics estrogen and is now banned but still persists in the environment). In both cases they found that male offspring had low sperm counts as adults, together with prostate disease, kidney disease, immune system abnormalities, testis abnormalities, tumor development, and hypercholesterolemia (high cholesterol). When these males did succeed in impregnating a female, she gave birth to sons who also had fewer sperm and the same panoply of defects.⁹¹

Mike’s group continued breeding the animals and found that the effects persisted until the F4 generation and beyond. This was the first demonstration that an environmental chemical had heritable, transgenerational effects. Because these defects intensified in the F3 group and its descendants, there is no possibility that genetic mutations were to blame. Instead, these effects were “epigenetic,” which literally means “on top of genetics.” Mike’s hypothesis is that altered DNA methylation patterns—not genetic mutations in the DNA itself—were probably to blame.⁹² Let me explain.

As we will discuss at length in the next chapter, DNA methylation is one way through which the expression of our genes is controlled without changing the DNA sequence. This is the essence of epigenetics. The changes in the epigenome are called “epigenetic marks” or “epimutations,” and these are “read” by the transcription machinery in the cells, influencing whether the gene should be expressed or not. These epigenetic marks are important for our health and longevity and also how these traits are passed on to future generations.

While the concept of epigenetics is becoming well established, the new science studying the way that environmental factors influence gene expression is taking longer to be fully accepted because it harkens back to the two-hundred-year-old studies of Jean-Baptiste Lamarck. Lamarck believed that acquired characteristics could be inherited; he was wrong about the details of his theory (for example, that giraffes evolved from antelopes by stretching their necks and passing the longer necks to their offspring), but transmitting the effects of environmental exposures to our offspring is similar to Lamarck’s theory about the inheritance of acquired traits. The opposite (dominant) theory—that inheritance is controlled entirely by our genes—is called genetic determinism.

Mike Skinner can tell many stories about his ongoing battles with the scientific orthodoxy to convince them that environmental epigenetics is a valid theory that should be incorporated into our thinking. This is always the fate of radical new theories: it takes quite a while before they are accepted by the scientific establishment. If you think about it, this is appropriate (although frustrating for the innovators) because we should not change long-standing, well-supported theories without strong, reproducible evidence. In the case of environmental epigenetics, that evidence is growing by the day.

At about the same time we were performing our transgenerational experiments with TBT, Mike and his group were screening a host of other environmental chemicals and pollutants for potential transgenerational effects. These included jet fuel, plastics ingredients, and more pesticides.⁹³^,⁹⁴ Once again, he noted that exposed animals had reproductive problems and quite a few other effects that were also passed down the generations. This time, however, they saw something new in their F3 animals: about 10 percent of the descendants of the F0 females injected with a mixture of BPA and phthalates were obese. This was not observed in the F1 and F2 generations, which were directly exposed to the chemicals, or in the control, unexposed animals. F3 animals were not exposed, which suggests that the transgenerational inheritance is mediated by epigenetic changes caused by the original exposure in the F0 animals that became apparent only when the effects of the direct exposure were gone. At least this is Mike’s argument. These results were interesting, but not nearly as striking as the results Mike’s team found when they tested DDT, the famous EDC pesticide. As was the case in the vinclozolin and methoxychlor experiments mentioned earlier, the F1 and F2 generations suffered a variety of abnormalities but were of normal weight. Remarkably, a full 50 percent of F3 animals—both male and female—were obese.⁹⁵

Mike began to connect the dots in his head, considering both the marked rise in obesity rates among U.S. adults over the past few decades and pregnant women in the 1950s and 1960s who were exposed to DDT. There probably was not a woman who was pregnant in the 1950s or 1960s who was not exposed to DDT. Could the exposures in the 1950s have anything to do with the prevalence of obesity among adults today? We may never know for sure, because the kinds of experiments required to show this conclusively in humans are unethical to conduct (we cannot, nor do we want to, do double-blind, placebo-controlled clinical trials on humans using toxic chemicals), and the longest-running study of a human population that might demonstrate strong correlations between DDT exposure and obesity—the San Francisco Kaiser Permanente cohort—is now only in the F2 generation. But it is an intriguing observation nonetheless.

Although DDT is banned in the United States, it is still used in specific areas (for instance, in Africa) for controlling mosquitoes carrying pathogens such as malaria and dengue fever. So the possibility that DDT may cause transgenerational effects on obesity is a very real concern. The observation that multiple EDCs can cause transgenerational effects, including obesity, is something that needs to be addressed by regulatory agencies worldwide. Sadly, the wheels of government move very slowly indeed.

OBESOGENS AND NUCLEAR HORMONE RECEPTORS

As I briefly mentioned earlier, many endocrine disruptors act on nuclear hormone receptors to activate or inactivate them inappropriately. As we also discussed, EDCs that act as estrogen mimics can predispose animals to obesity. For instance, diethylstilbestrol (DES) is a potent estrogen that clearly exerts its effects through the estrogen receptors. Exposing a female fetus or newborn to DES will lead to massive weight gain later in life, but exposure to DES or other estrogens later in life leads to the opposite effect—leanness. Like DES, BPA also binds to estrogen receptors in the body, but we don’t know whether it causes weight gain through estrogen receptors or some other receptors that it influences.

De-Kun Li, an epidemiologist and senior research scientist at Kaiser Permanente in Oakland, California, has also documented a relationship between BPA and obesity. He found that among school-age children in China, preteen girls (not boys, just as in mice) with higher BPA levels in their urine were more likely to be higher in weight, too.⁹⁶ In fact, after adjusting for potential confounders, a higher urine BPA level—at the level corresponding to the median urine BPA level in the U.S. population—was associated with more than double the risk of being at a weight greater than the 90th percentile among girls who were nine to twelve years old. Unfortunately, cross-sectional studies such as these, which measure chemical exposures and outcomes at a single time in life, cannot tell us whether the exposure preceded obesity. We need to follow people throughout their lifetime (longitudinal studies) to get closer to understanding causation.

INSULIN AND LEPTIN RESISTANCE: MORE WAYS THAT OBESOGENS CAN MAKE US FAT

To be sure, not all EDCs are obesogens, and not all obesogens are EDCs. For example, high-fructose corn syrup could be considered an obesogen as a result of its effects on metabolism and potential to increase body fat, but it is technically not an EDC. It does not disrupt the function of any nuclear hormone receptors, particularly the estrogen, androgen, and thyroid hormone receptors that the EPA associates with endocrine disruption.ⁱⁱⁱ Similarly, the widely used agricultural weed killer atrazine, which contaminates water supplies throughout the Midwest, is an EDC but probably not an obesogen. It can negatively impact your hormones but as far as we know not in a way that will lead to weight gain.

It is important to understand that the biological mechanisms by which EDCs exert their effects are not mutually exclusive. EDCs can have direct effects on a particular target tissue by disrupting a specific receptor pathway, but they can also lead to widespread, sometimes subtle effects on multiple organ systems that ultimately promote obesity in the exposed individual and in subsequent generations. While we may have evidence that certain chemical obesogens cause animals to become obese or diabetic, we do not always know what biological pathways lead to this outcome. Research to date suggests that not all obesogens operate the same in the body even though the outcome—weight gain—is the same. We are fairly certain that TBT and triflumizole act through PPARγ, although they may also have other targets.

Although DDT is known to act like an estrogen, and DDE, the major breakdown product of DDT, counteracts the effects of male sex hormones such as testosterone (an antiandrogen), we are not sure how DDT promotes obesity in Mike Skinner’s F3 rats. We don’t know how many obesogens elicit heritable effects and whether these are carried by altered DNA methylation, histone methylation, or some other mechanism (we will come back to this in the next chapter). Whether a chemical can elicit permanent changes that can be passed on to the next generation of children and whether exposure occurs during a critical window of development (when germ cells are being programmed) can determine whether the effects of an obesogen will be temporary or permanent and transmitted throughout multiple generations.

In addition to reprogramming stem cells and encouraging the body to store more fat, EDCs could be promoting obesity in at least three other ways. One is by prompting cells to become insulin resistant, which makes the pancreas pump out more insulin to control blood sugar, leading to increased fat storage all over the body. Translation: You are more likely to turn the foods you eat into body fat. A second is by preventing the satiety hormone leptin from telling your body that you have had enough to eat. As mentioned, EDCs can make cells resistant to the leptin signal, thereby fueling weight gain. A third is that EDCs can inhibit the function of thermogenic brown fat. Although these possible mechanisms need to be better understood through future research, they are indeed credible. Let’s start with the perils of insulin resistance.

If your body is no longer sensitive to insulin you will be on the road to experiencing serious metabolic issues, including diabetes, because insulin is the main hormone responsible for maintaining blood sugar balance. Weighing approximately 3.3 pounds in adults, the liver is the largest and most metabolically complex organ in the human body. Liver cells (hepatocytes) make up more than 80 percent of total liver mass and play a critical role in metabolism. The liver is the principal location of glucose storage as glycogen and the main source of glucose for all tissues of the body. (Recall from the previous chapter that glucose is a preferred source of energy.) Because the pancreatic veins drain into the portal venous system, every hormone secreted by the pancreas must traverse the liver before entering the circulation. The liver is a major target for pancreatic insulin and glucagon, the hormone that promotes the breakdown of glycogen to glucose in the liver. The liver is also where these hormones are removed from circulation and broken down. The body is about 40 percent by weight of skeletal muscle (30 to 40 percent in women, 40 to 50 percent in men), which is the major user of glucose in the body other than the brain.

One function of insulin is to stimulate storage of glucose as glycogen when glucose levels in the blood are high. When insulin levels in the blood go down, the body triggers glycogen breakdown so glucose can be released into the bloodstream for use as energy. If obesogens prompt the body to become insulin resistant, you may not be able to convert glucose to glycogen effectively, and glucose levels in the blood may rise to excessive levels. The pancreas responds by pumping out increasing levels of insulin, which promote fat storage and can trigger diabetes. If you are diabetic, by definition you have high blood sugar because your body cannot move glucose into cells, where it can be safely stored for energy. And if it remains in the blood, that excess sugar can damage most of the body, including kidneys, blood vessels, skin, cardiovascular system, and nervous system. Excess sugar also speeds cellular aging by binding to proteins, creating what are called advanced glycation end products (AGEs, for short), which are very damaging to cellular function.⁹⁸

Keep in mind that insulin is a multitasker. When its levels are high and blood sugar cannot be managed well, it contributes to other biological processes. Insulin is an anabolic hormone that stimulates growth, promotes fat formation and retention, and encourages inflammation. When insulin levels are high, thyroid hormone, estrogen, progesterone, and testosterone homeostasis can also be destabilized. In turn, all of these imbalances have downstream negative effects on multiple body systems, including metabolism. These broader effects of excess insulin make restoring bodily balance (homeostasis) all the more difficult, even broken beyond repair.

Another way that EDCs may be acting to promote obesity is by causing leptin resistance, another co-conspirator in weight gain. Leptin is produced by your white fat cells and signals to leptin receptors in your hypothalamus, the part of the brain where your inner reptile lives. This ancient structure that predates humans (and even dinosaurs) is responsible for rhythmic activities (for instance, sleep-wake cycles) and a broad range of physiological functions in your body from hunger to sex. Broadly speaking, the more you can increase how sensitive your body is to leptin, the more normal your weight will be. By “sensitivity,” I mean how leptin receptors in your brain recognize and use leptin to carry out various operations. When fat cells start to fill up and expand, they secrete leptin to tell your body that you have stored enough fat. Once the fat cells begin to shrink as their contents are burned for energy, the leptin faucet is slowly turned off. Eventually you are able to feel hunger again and the cycle starts all over. This is but one example of the many different mechanisms the body has to expertly manage energy metabolism in the name of survival. People with naturally low levels of leptin are prone to overeating. An important study published in 2004 showed that people with a 20 percent drop in leptin levels (due to sleep deprivation) experienced a 24 percent increase in hunger and appetite, driving them toward caloriedense, high-carbohydrate foods, especially foods with a lot of sugar, starch, and salt.⁹⁹

One more recently identified mechanism of obesogen action is to inhibit thermogenesis. Michele La Merrill and her colleagues at the University of California–Davis showed that prenatal and early postnatal exposure of rats to DDT led to reduced core body temperature in adulthood, together with decreased energy expenditure and intolerance to cold.¹⁰⁰ Intriguingly, the exposed animals developed signs of metabolic dysfunction when exposed to a high-carbohydrate diet that was similar to what is seen in humans with metabolic syndrome (prediabetes). These included glucose intolerance together with elevated levels of insulin and lipoproteins in the blood. This is the first demonstration that an obesogen can function by making the body essentially use less energy and not respond to normal environmental signals such as cold. I have no doubt that other obesogens will be identified that make us fat by reducing the “burning” of some of the calories we consume.

OBESOGENS AND METABOLIC SET POINTS

One area of my work looks at the potential consequences of obesogens on metabolic set points. As you may recall, a metabolic set point is the body’s internal control mechanism that regulates metabolism to maintain a certain level of body fat that is regulated by the hypothalamus. We once thought that a person’s metabolic set point was primarily genetically determined at birth and remained throughout life, but obesogens are changing the story.

Obese humans have more fat cells and probably developed them early in life by mechanisms I have been describing thus far in the book. We know that the minimum number of fat cells a person will have is programmed early in life. Fat cells develop beginning at the fourteenth week of human gestation, and the number of fat cells increases through adolescence. The number is largely fixed after that. If individuals are exposed to fat-inducing stimuli, such as obesogens, during this sensitive window of development, this can permanently increase their fat cell number ⁹⁰ and thereby change their metabolic set point.⁷⁷ If this is true, as appears to be the case, the implications for weight gain are profound. The higher number of fat cells from the beginning of life cannot be reduced by diet, exercise, or even surgery—your body will defend this number of fat cells and add them back if you remove them, although not necessarily in the same place they were before. The amount of visceral fat can be expanded in adults via proliferation of those fat cells, but permanently decreasing fat cell number by weight loss has not been documented. It is an unfair one-way street: you can gain more fat cells, but as far as we know, you can never lose those fat cells no matter how diligently you diet or exercise.

Diligent and stoic adherence to a restrictive diet and a vigorous exercise regimen can successfully shrink, or even empty, existing fat cells. There is no evidence that empty fat cells automatically undergo cellular suicide (apoptosis). It would not make good evolutionary sense for this to happen anyway because healthy fat cells would be required for the organism to survive periods of famine or fasting. Moreover, it is likely that shrunken fat cells would “crave to be filled” because expression of the satiety hormone, leptin, closely parallels fat mass, and small fat cells secrete the least leptin. This means that the more fat cells you have, the harder it will be to succeed at long-term weight loss; therefore, the sooner you can reduce your contact with obesogens, the better.

A staggering 83 to 87 percent of those who work extremely hard to achieve significant weight loss regain the weight within a few years.³⁸^,³⁹ Why would they work so hard to achieve major weight loss, only to forget what they had learned and revert to their original, fatter self? This does not make much sense, except viewed through the lens of altered metabolic set points. A very recent study of people who lost massive amounts of weight during a season of The Biggest Loser and then regained it showed that these contestants had metabolic set points that were permanently programmed for the worst.⁵⁷ So much so that in order for them to maintain their weight loss, they would have to dramatically and permanently restrict their caloric intake and exercise many hours a day.

In my lab, Raquel Chamorro-García tested the effects of changing diet composition on F4 mice, whose F0 ancestors had been exposed to TBT throughout pregnancy and lactating.⁷⁷ At nineteen weeks of age, both TBT and control mice had about the same percentage of body fat on a normal, low-fat diet (13.2 percent calories from fat). She then switched the mice to a slightly higher-fat diet (21.6 percent calories from fat), although this still qualifies as a low-fat diet. Remarkably, the TBT mice gained weight very fast on the new diet compared with controls, becoming obese within six weeks. Moreover, when she fasted the animals, those whose ancestors had been exposed to TBT lost less fat than did the control animals. In short, the TBT animals handled calories differently; they gained weight more quickly and then resisted losing fat even during fasting—every dieter’s lament. We do not yet know precisely how, but understanding which genes we have altered and in what way they are changed is the top priority in my research at the moment. Our working hypothesis is that obesogen exposure causes large-scale changes in how DNA is arranged in the nucleus, which leads to altered DNA methylation resulting in leptin resistance and a predisposition to higher expression of obesity-related genes.⁹⁰ In other words, this changed DNA structure leads to certain biological “switches” being turned on or off, predisposing the TBT animals to store fat and to resist mobilizing it.

In 2015, a team of researchers at Yale University School of Medicine led by Matthew Rodeheffer published a study that further revealed how the body can respond to a high-fat diet. They showed that in contrast to what had been believed, a high-fat diet can induce the production of more visceral fat cells, even when the existing cells are not yet full.¹⁰¹ Visceral fat cells are the belly fat cells that surround the liver and other abdominal or visceral organs, such as the kidneys, pancreas, heart, and intestines. As we discussed in chapter 2, this type of fat is the most devastating to our health. In their paper, Rodeheffer and colleagues explain that when the mice were fed a high-fat diet, their visceral fat mass increased and they formed new fat cells before existing fat cells were filled up. This finding was opposite to the common dogma that new fat cells are not formed until existing cells are filled. I am fairly certain that future studies will show that obesogens have the same effect as a purely diet-induced obesity—increasing the number of visceral fat cells. And as we will see in chapter 5, obesogens can also change the intestinal microbiome to further disrupt metabolism and balance of fat storage in the body.

THE CHALLENGES OF OBESOGEN RESEARCH: WHY CAN’T WE KNOW MORE AND REGULATE MORE?

As we scientists continue to amass data on the effects of obesogens in laboratory tests and in animal models, a good question remains: How are these compounds affecting humans? As I mentioned, getting high-quality, long-term data on the relationships between chemicals and obesity in humans is challenging. Not only is it expensive and time-consuming, but in many respects it is impossible to unequivocally demonstrate cause and effect because, as mentioned, it is unethical to conduct controlled exposures of humans to toxic chemicals as we do for drugs. The best evidence for the effects of chemicals on humans comes from accidental exposures, as noted earlier, and from experiments using animal models. As a result, regulators struggle to determine acceptable exposure levels for the chemicals, and the obesogen field remains on the sidelines of environmental policy and clinical practice.

The Toxic Substances Control Act of 1976 (TSCA) is old and out-of-date; it has not kept up with science, and the vast majority of chemicals that are approved for use under the TSCA were never tested for safety in any way, let alone for endocrine activity. Chemicals in use when the TSCA was passed were “grandfathered”—that is, they were assumed to be safe without testing to prove it. Its replacement, the Frank R. Lautenberg Chemical Safety for the 21st Century Act (S.697), is worse in many ways. Perhaps most egregiously, it removes the power of individual states to regulate chemicals, instead mandating a uniform, nationwide policy that will be approved by the EPA, should the EPA continue to exist in the new political climate. This is a major victory for chemical companies who lobbied hard for this provision, but a catastrophic blow for chemical safety. Why do I say this?

The EPA has not tried to outlaw a chemical under the TSCA since the 1980s. Since the TSCA was enacted forty years ago, the EPA has banned only five existing chemicals (of more than eighty-six thousand in common use) as posing unreasonable risk to human health. These are polychlorinated biphenyls (PCBs), chlorofluoroalkanes (CFCs), dioxin, asbestos, and hexavalent chromium (made famous by Erin Brockovich). However, even these efforts have not been successful, since the asbestos industry successfully challenged the asbestos ban. The EPA has a program intended to test chemicals for endocrine disruption, the Endocrine Disruptor Screening Program, which was mandated by the Food Quality Protection Act of 1996 and an amendment to the Safe Drinking Water Act passed in the same year. But the first orders for initial testing of chemicals for endocrine disrupting activity were not issued until 2009. Worse yet, many of the approved tests were developed decades ago and are relatively insensitive to EDC action. Although scientists in the EDC research community have identified nearly one thousand chemicals with endocrine disrupting activity, the chemical industry disputes these findings, and as of September 2017, the EPA has not banned or regulated a single chemical based on its endocrine disrupting activity. Interestingly, the FDA has banned the antibacterial agent triclosan because it is an EDC. This is a sorry state of affairs.

Unlike other nations, the United States operates under the policy that a substance is deemed safe until proven otherwise. That is, the burden is on the EPA to prove that a chemical is hazardous to humans before it can be banned. While it may make sense to allow a hundred guilty men to go free rather than send one innocent man to jail (the origin of the presumption of innocence concept), it makes no sense at all in regulating chemicals. This position stands in stark contrast to the policy in Europe, where the burden of proof is on the company to prove that a chemical is safe before it can be licensed. Therefore, it behooves us to operate under a totally different personal policy—one that I will be outlining in part 2.

But before I get to that personal policy, there is one more important piece of the obesogen story that must be addressed: the power of epigenetics. In the past few years, research has exploded on how behavioral and environmental factors change how our genes are expressed. Obesogens are probably not mutating our DNA, but they could be changing how the genes encoded by our DNA are being expressed. Let me explain.

CHAPTER 3

The Science of Obesogens

Why Chemicals—Not Willpower—Could Be Holding the Remote Control to Your Weight