The Interplay Between Environmental Chemical Exposures and Obesity Proceedings of a Workshop (2016) / Chapter Skim
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4 Biological Pathways and Environmental Influences
4 Biological Pathways and Environmental Influences
Pages 45-76
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From page 45... ...
HIGH-THROUGHPUT SCREENING OF ENVIRONMENTAL CHEMICALS The first speaker in the session was Scott Auerbach, a molecular toxicologist with the National Toxicology Program (NTP) of the National Institute of Environmental Health Sciences (NIEHS)
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From page 46... ...
. Then, in 2008, Tox21 and ToxCast joined forces to form the "Tox21 community." The Tox21 community had several goals: to identify patterns of compound-induced biological responses to characterize toxicity and disease pathways, facilitate cross-species extrapolation, and model lowdose extrapolation; to prioritize compounds for more extensive toxicological evaluation; and to develop models that could predict the biological response in humans.
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From page 47... ...
The second approach being used to mine the Tox21 data is what Auerbach called the "sentinel chemical correlation." This approach is purely data driven, he said, and does not involve input from experts. The approach is based on a particular premise: chemicals that exhibit similar biological properties across high-throughput screening assays will likely exhibit similar biological properties in vivo.
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From page 48... ...
To make the tool even more valuable, the developers created a collection of chemical-to-biological annotations for the various chemicals in the data set. This makes it possible to do "chemical annotation enrichment analysis," which is similar in spirit to the commonly used gene annotation enrichment analysis.
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"Part of the challenge that we are dealing with is the lower-potency environmental chemicals," he said. "What I can tell you from reviewing the Tox21 data is that pharmacology works.
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In particular, epidemiological studies have found that if you examine death rates among people with very high levels of POPs in their blood, people who are obese have a significantly lower risk of death than thin people. Of course, among those with low levels of POPs in their blood, the obese are at a high risk of dying, but having large amounts of fat tissue does seem to have a protective effect against the toxicity of POPs (see Figure 4-1)
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2 Buut what happ pens in the lo ong run to obbese people whose adipoose tissue has stored to oxic chemicaals? They maay be protected from acuute exposu ures, but whaat happens if the chemicalls stored in thhe fat tissue aare later reeleased?
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From page 52... ...
that could explain part of it, but this is still a paradox, I have to say." Barouki also noted that other researchers have also observed higher levels of POPs in the blood of people who have experienced long-term weight loss. The bottom line, he said, is that adipose tissue plays an important role in protecting against acute exposure to environmental chemicals.
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"This is acute. It can provoke an increase in the inflammation of the adipose tissue and the invasion by macrophages." Barouki also mentioned recent work by a colleague, Jerome Ruzzin, who has studied the levels of POPs in metabolically abnormal versus metabolically healthy obese individuals (Gauthier et al., 2014)
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But over time the adipose tissue can release the POPs into the bloodstream, potentially leading to chronic problems elsewhere in the body. On the flip side -- talking about how POPs affect adipose tissue rather than how adipose tissue affects POPs -- Barouki said that the data indicate that POPs result in a relatively acute effect on the inflammation of the adipose tissue and probably have some metabolic effects as well.
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exposure cause weight gain," he
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PPARγ expression in a mesenchymal stem cell commits it to the adipocyte lineage, Blumberg said, while PPARγ knockout commits it to the bone lineage. Tributyltin's Transgenerational Effects The first experiments that Blumberg's group carried out examined what happened to mesenchymal stem cells when mice were exposed prenatally to tributyltin or to rosiglitazone.
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Furthermore, all three generations of mice, but particularly the third-generation mice, had substantially higher levels of expression of fat-related genes in the mesenchymal stem cells than control mice. In other words, the genes related to the production of fat cells were much more active in the exposed mice and their descendants than in unexposed mice.
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Indeed, 50 nanomolar tributyltin is vastly more potent than 500 nanomolar rosiglitazone. In terms of the actions of individual genes, PPARγ does not push mesenchymal stem cells to commit to becoming fat cells.
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Furthermore, prenatal exposure to tributyltin permanently alters the adult phenotype, and it recruits mesenchymal stem cells to the adipocyte lineage and diverts them away from the bone lineage. However, Blumberg continued, a key question is whether humans are exposed to sufficient levels of tributyltin to lead to these effects, and that is controversial.
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The existence of transgenerational effects raises the stakes for the argument concerning which chemicals should be regulated and which standard should be used to determine which chemicals should be taken off the market, Blumberg said. "That is not a decision for me to make, but that is a discussion that we need to have." Discussion In the question-and-answer session following Blumberg's presentation, Robert Barouki asked Blumberg about the body composition of the lab animals that gained body fat without gaining weight.
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Jerry Heindel of NIEHS commented that the key element in the obesogen hypothesis is that exposure to a chemical must alter a person's set point or sensitivity for gaining weight. Up to now, he said, no one had demonstrated a potential obesogen that changed the set point in this way, but Blumberg's experiments with the higher-fat diet pushing tributyltinexposed mice, even in the fourth generation, to gain weight when controls did not was just such a demonstration, Heindel said.
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So in carrying out their research, Rubin and her colleagues had a series of questions that they wished to answer: Does developmental exposure to BPA alter body weight and body composition and contribute to other associated components of metabolic disease? What BPA doses cause weight gain and increased fat mass?
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Something very similar was seen in females exposed perinatally and peripubertally. The females exposed to 2.5 micrograms per kilogram of body weight had the largest amount of fat mass, while those given doses of 250 micrograms per kilogram of body weight had noticeably less fat mass, and, indeed, there was little difference between the control animals and the mice given 250 micrograms per kilogram of body weight.
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"It was most effective for the males, probably not the best choice for the females, but we had to make a decision." They took littermates matched for body weight and body composition at 8 weeks of age. One male and one female from each litter were on the high-fat diet, and one male and one female from the same litter were placed on the normal chow diet for the remainder of the study.
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All these effects of BPA on body weight, body composition, and elements of metabolic disease differed by BPA dose, sex, exposure window, and diet, Rubin said. Future Work Since she and her colleagues began this work, Rubin said, there has been a growing body of data from studies with mice and rats that corroborate their findings that early BPA exposure may act as an obesogen, may alter body composition and glucose homeostasis, and may affect liver function.
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Finally, she said, BPA seems to alter metabolic pathways. Rubin concluded by saying that she and her colleagues are working to determine exactly what kinds of changes are occurring in metabolic pathways that influence body weight.
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"I believe what we are looking at is the macrophages coming in to clean up the mess," she said. EFFECTS OF ENVIRONMENTAL CHEMICALS ON ENERGY METABOLISM AND INSULIN SECRETION The final speaker in this session was Barbara Corkey, the Zoltan Kohn Professor of Medicine and Biochemistry at the Boston University School of Medicine.
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It has been known for a long time that insulin downregulates its receptor. Inhibition of the secretion of insulin improves insulin resistance and increases weight loss, and under all of these different manipulations of insulin, which is supposed to be controlling glucose, normal glucose levels are maintained.
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potential cause of metabolic disease." To discover what environmental agents might be causing beta cell hypersecretion of insulin, which would then lead to hyperinsulinemia, obesity, diabetes, and insulin resistance, Corkey and her colleagues began to do high-throughput screening of a variety of agents. "It did not last very long because the hit rate was so high," she said.
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Corkey and her colleagues examined various known molecular steps involved in glucose-induced insulin secretion and did not find any that were triggered by these various agents. What they did find, however, was that both monoglycerides and glucose lead to a change in redox state in rat islets.
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They have also shown that changes in the redox state alter function in fat cells and, as described above, beta cells. The bottom line, she said, "is that there is a circulating system that is a reflection of the metabolic state that informs all the cells in the body of what this situation is." Although she has not yet done the experiments, she said that she expects that when she tests toxic or obesogenic agents in the same way, they will change the parameters in the bloodstream, which will then have an effect on all the various cells that are sensitive to such changes.
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None of them has worked." Xiaoyan Pang from the University of Illinois suggested that there is a good reason why a single environmental agent circulating through the body would affect different tissues or cell types differently. The various epigenomes among individuals may explain different tissue responses, Pang said.
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"One of the things about the chemical enrichment analysis or the sentinel chemical analysis is that it goes after one specific mechanism typically because you pick a prototype chemical," he said. "I picked rosiglitazone, which is a wellknown PPARγ activator, … whereas with the ToxPi approach, we take into account all the assays that the experts have recommended.
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Auerbach commented that when he searched through the side effects of various pharmaceutical drugs to look for drugs known to cause weight gain and obesity, he found that 90 percent of such drugs were neuroactive substances. So, yes, some environmental chemicals are likely to have direct effects on the brain, but it is harder to study such effects, he said, because it is difficult to characterize behavior, he said.
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The same is true of greasy molecules and amino acids. "Generally speaking," he explained, "those are the rules of the blood–brain barrier." Al McGartland of EPA asked what it would take to get a dose– response curve for humans, rather than lab animals, that would apply to a subpopulation in the United States.
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1999. Exogenous hyperinsulinemia causes insulin resistance, hyperendothelinemia, and subsequent hypertension in rats.
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