Review

. 2022 May:199:115015.

doi: 10.1016/j.bcp.2022.115015. Epub 2022 Apr 5.

Obesity II: Establishing causal links between chemical exposures and obesity

Jerrold J Heindel¹, Sarah Howard², Keren Agay-Shay³, Juan P Arrebola⁴, Karine Audouze⁵, Patrick J Babin⁶, Robert Barouki⁷, Amita Bansal⁸, Etienne Blanc⁷, Matthew C Cave⁹, Saurabh Chatterjee¹⁰, Nicolas Chevalier¹¹, Mahua Choudhury¹², David Collier¹³, Lisa Connolly¹⁴, Xavier Coumoul⁷, Gabriella Garruti¹⁵, Michael Gilbertson¹⁶, Lori A Hoepner¹⁷, Alison C Holloway¹⁸, George Howell 3rd¹⁹, Christopher D Kassotis²⁰, Mathew K Kay¹², Min Ji Kim²¹, Dominique Lagadic-Gossmann²², Sophie Langouet²², Antoine Legrand²¹, Zhuorui Li²³, Helene Le Mentec²¹, Lars Lind²⁴, P Monica Lind²⁵, Robert H Lustig²⁶, Corinne Martin-Chouly²¹, Vesna Munic Kos²⁷, Normand Podechard²¹, Troy A Roepke²⁸, Robert M Sargis²⁹, Anne Starling³⁰, Craig R Tomlinson³¹, Charbel Touma²¹, Jan Vondracek³², Frederick Vom Saal³³, Bruce Blumberg²³

Affiliations

¹ Healthy Environment and Endocrine Disruptor Strategies, Commonweal, Bolinas, CA 92924, USA. Electronic address: jerryheindel@gmail.com.
² Healthy Environment and Endocrine Disruptor Strategies, Commonweal, Bolinas, CA 92924, USA.
³ Health and Environment Research (HER) Lab, The Azrieli Faculty of Medicine, Bar Ilan University, Israel.
⁴ Department of Preventive Medicine and Public Health University of Granada, Granada, Spain.
⁵ Department of Systems Biology and Bioinformatics, University of Paris, INSERM, T3S, Paris France.
⁶ Department of Life and Health Sciences, University of Bordeaux, INSERM, Pessac France.
⁷ Department of Biochemistry, University of Paris, INSERM, T3S, 75006 Paris, France.
⁸ College of Health & Medicine, Australian National University, Canberra, Australia.
⁹ Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY 40402, USA.
¹⁰ Environmental Health and Disease Laboratory, University of South Carolina, Columbia, SC 29208, USA.
¹¹ Obstetrics and Gynecology, University of Cote d'Azur, Cote d'Azur, France.
¹² College of Pharmacy, Texas A&M University, College Station, TX 77843, USA.
¹³ Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
¹⁴ The Institute for Global Food Security, School of Biological Sciences, Queen's University, Belfast, Northern Ireland, UK.
¹⁵ Department of Endocrinology, University of Bari "Aldo Moro," Bari, Italy.
¹⁶ Occupational and Environmental Health Research Group, University of Stirling, Stirling, Scotland.
¹⁷ Department of Environmental and Occupational Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY 11203, USA.
¹⁸ McMaster University, Department of Obstetrics and Gynecology, Hamilton, Ontario, CA, USA.
¹⁹ Center for Environmental Health Sciences, Mississippi State University, Mississippi State, MS 39762, USA.
²⁰ Institute of Environmental Health Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48202, USA.
²¹ Sorbonne Paris Nord University, Bobigny, INSERM U1124 (T3S), Paris, France.
²² Univ Rennes, INSERM EHESP, IRSET UMR_5S 1085, 35000 Rennes, France.
²³ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
²⁴ Clinical Epidemiology, Department of Medical Sciences, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
²⁵ Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
²⁶ Division of Endocrinology, Department of Pediatrics, University of California San Francisco, CA 94143, USA.
²⁷ Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden.
²⁸ Department of Animal Science, School of Environmental and Biological Science, Rutgers University, New Brunswick, NJ 08901, USA.
²⁹ Division of Endocrinology, Diabetes and Metabolism, The University of Illinois at Chicago, Chicago, Il 60612, USA.
³⁰ Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³¹ Norris Cotton Cancer Center, Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
³² Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic.
³³ Division of Biological Sciences, The University of Missouri, Columbia, MO 65211, USA.

PMID: 35395240
PMCID: PMC9124454
DOI: 10.1016/j.bcp.2022.115015

Review

Obesity II: Establishing causal links between chemical exposures and obesity

Jerrold J Heindel et al. Biochem Pharmacol. 2022 May.

. 2022 May:199:115015.

doi: 10.1016/j.bcp.2022.115015. Epub 2022 Apr 5.

Authors

Affiliations

¹ Healthy Environment and Endocrine Disruptor Strategies, Commonweal, Bolinas, CA 92924, USA. Electronic address: jerryheindel@gmail.com.
² Healthy Environment and Endocrine Disruptor Strategies, Commonweal, Bolinas, CA 92924, USA.
³ Health and Environment Research (HER) Lab, The Azrieli Faculty of Medicine, Bar Ilan University, Israel.
⁴ Department of Preventive Medicine and Public Health University of Granada, Granada, Spain.
⁵ Department of Systems Biology and Bioinformatics, University of Paris, INSERM, T3S, Paris France.
⁶ Department of Life and Health Sciences, University of Bordeaux, INSERM, Pessac France.
⁷ Department of Biochemistry, University of Paris, INSERM, T3S, 75006 Paris, France.
⁸ College of Health & Medicine, Australian National University, Canberra, Australia.
⁹ Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY 40402, USA.
¹⁰ Environmental Health and Disease Laboratory, University of South Carolina, Columbia, SC 29208, USA.
¹¹ Obstetrics and Gynecology, University of Cote d'Azur, Cote d'Azur, France.
¹² College of Pharmacy, Texas A&M University, College Station, TX 77843, USA.
¹³ Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
¹⁴ The Institute for Global Food Security, School of Biological Sciences, Queen's University, Belfast, Northern Ireland, UK.
¹⁵ Department of Endocrinology, University of Bari "Aldo Moro," Bari, Italy.
¹⁶ Occupational and Environmental Health Research Group, University of Stirling, Stirling, Scotland.
¹⁷ Department of Environmental and Occupational Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY 11203, USA.
¹⁸ McMaster University, Department of Obstetrics and Gynecology, Hamilton, Ontario, CA, USA.
¹⁹ Center for Environmental Health Sciences, Mississippi State University, Mississippi State, MS 39762, USA.
²⁰ Institute of Environmental Health Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48202, USA.
²¹ Sorbonne Paris Nord University, Bobigny, INSERM U1124 (T3S), Paris, France.
²² Univ Rennes, INSERM EHESP, IRSET UMR_5S 1085, 35000 Rennes, France.
²³ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
²⁴ Clinical Epidemiology, Department of Medical Sciences, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
²⁵ Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
²⁶ Division of Endocrinology, Department of Pediatrics, University of California San Francisco, CA 94143, USA.
²⁷ Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden.
²⁸ Department of Animal Science, School of Environmental and Biological Science, Rutgers University, New Brunswick, NJ 08901, USA.
²⁹ Division of Endocrinology, Diabetes and Metabolism, The University of Illinois at Chicago, Chicago, Il 60612, USA.
³⁰ Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³¹ Norris Cotton Cancer Center, Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
³² Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic.
³³ Division of Biological Sciences, The University of Missouri, Columbia, MO 65211, USA.

PMID: 35395240
PMCID: PMC9124454
DOI: 10.1016/j.bcp.2022.115015

Erratum in

Corrigendum to "Obesity II: Establishing causal links between chemical exposures and obesity" [Biochem. Pharmacol. 199 (2022) 115015].
Heindel JJ, Howard S, Agay-Shay K, Arrebola JP, Audouze K, Babin PJ, Barouki R, Bansal A, Blanc E, Cave MC, Chatterjee S, Chevalier N, Choudhury M, Collier D, Connolly L, Coumoul X, Garruti G, Gilbertson M, Hoepner LA, Holloway AC, Howell G 3rd, Kassotis CD, Kay MK, Kim MJ, Lagadic-Gossmann D, Langouet S, Legrand A, Li Z, Le Mentec H, Lind L, Lind PM, Lustig RH, Martin-Chouly C, Munic Kos V, Podechard N, Roepke TA, Sargis RM, Starling A, Tomlinson CR, Touma C, Vondracek J, Vom Saal F, Blumberg B. Heindel JJ, et al. Biochem Pharmacol. 2022 Aug;202:115144. doi: 10.1016/j.bcp.2022.115144. Epub 2022 Jun 14. Biochem Pharmacol. 2022. PMID: 35714447 No abstract available.

Abstract

Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.

Keywords: Adipocyte differentiation; Endocrine disruptor; Obesity; Obesogen; Weight gain.

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Figures

**Fig. 1.. Sources of obesogens.**
This figure shows just some of the major classes of obesogens along with some sources of exposure. Exposure to obesogens occurs at home and work; via the air, water, food and skin contact.

**Fig. 2.. Epigenetic regulation of obesity**
Chemicals shown are just representatives of all of the classes of chemicals that are obesogens, and that can act via alterations in epigenetic control of gene expression, especially when exposures occur during development when hormones and growth factors are controlling cell and tissue differentiation. The known epigenetic control systems are shown: DNA methylation, Histone modification, chromatin modeling, and a variety of noncoding RNAs.

**Fig. 3.. BPA regulation of obesity**
BPA is an obesogen. The actions of BPA are the most detailed and comprehensive of all obesogens and this figure indicates the multiple sites and mechanisms whereby it was shown to act to stimulate weight gain from *in vitro* and animal model experiments.

**Fig. 4.. Classification of nutritive and non-nutritive sweeteners.**
There are a variety of nutritive and non-nutritive sweeteners. This classification scheme shows the different categories and where each nutritive and non-nutritive fall to help in understanding their chemical backbone and chemistry.

**Fig. 5.. Multiple actions of obesogens.**
Obesogens in addition to increasing the number and size of adipocytes also affect other tissues and process. Several of the main effects of obesogens are shown here. These are not all of the tissues and processes affected but show the broad effects of obesogenic chemicals. The chemicals shown have been reported to have that effect but that does not mean that other chemicals may not also have those effects. For example, the three chemicals shown are the only ones that have been examined for their effects on pathways and genes in adipocytes. It may be that other obesogens will also stimulate the production of dysfunctional adipocytes. Colors are only to highlight the same chemical across multiple mechanisms.

**Fig. 6.. Composite of sites and mechanisms of obesogens.**
Obesogens, as described in the text, can act via a variety of mechanisms and act on a variety of tissues. Some mechanisms are direct, such as receptor mechanisms and epigenetic changes and some, such as sirtuins, oxidative stress, inflammation, circadian rhythms, alterations in food intake and food addiction, and increase in number and size of fat cells, can result from the initial mechanisms. Obesogens have both direct and indirect actions on several tissues like liver, pancreas, muscle, gut microbiome, and brain. Thus, obesogens can disrupt all the sites and tissues known to be involved in control of metabolism.

See this image and copyright information in PMC

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Obesity II: Establishing causal links between chemical exposures and obesity

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Obesity II: Establishing causal links between chemical exposures and obesity

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