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      History of the Obesogen Field: Looking Back to Look Forward

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          Abstract

          The Obesogen field developed from two separate scientific research areas, endocrine disruptors and the Developmental Origins of Health and Disease (DOHaD). Endocrine Disrupting Chemicals (EDCs) are exogenous chemicals or mixtures of chemicals that interfere with the action of hormones. Exposure to EDCs during early development (DOHaD) has been shown to increase susceptibility to a variety of diseases including infertility, asthma, breast and prostate cancer, early puberty, susceptibility to infections, heart disease, autoimmune disease, and attention deficit hyperactivity disorder/learning disability. The effects of EDCs on obesity and fat cell development first gained attention around the turn of the twenty-first century. In 2002 Dr. Paula Baillie-Hamilton wrote the first review article focusing on environmental chemicals and obesity. She suggested that the obesity epidemic correlated with the increased production of chemicals after World War II. Baillie-Hamilton identified studies showing that exposures to a variety of chemicals led to weight gain. Shortly after that a commentary on an article showing that nonylphenol would increase fat cell differentiation in vitro noted the Baillie-Hamilton article and made the point that perhaps obesity was due in part to exposure to EDCs. In 2006 the field of DOHaD/EDCs and obesity made a giant leap forward when Dr. Bruce Blumberg published a paper showing that tributyltin could lead to weight gain in mice and coined the term obesogen for a chemical that caused weight gain and lead to obesity. In 2011, the NIEHS developed the first funding initiative focused on obesogens. In the following years there have been several workshops focused on obesogens. This paper describes these early days that lead to the obesogen hypotheses and the growth of the field for a decade, leading to its prominence today, and provides some insight into where the field is moving.

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          Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations

          Environmental compounds are known to promote epigenetic transgenerational inheritance of adult onset disease in subsequent generations (F1–F3) following ancestral exposure during fetal gonadal sex determination. The current study was designed to determine if a mixture of plastic derived endocrine disruptor compounds bisphenol-A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) at two different doses promoted epigenetic transgenerational inheritance of adult onset disease and associated DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to either the “plastics” or “lower dose plastics” mixture during embryonic days 8 to 14 of gonadal sex determination and the incidence of adult onset disease was evaluated in F1 and F3 generation rats. There were significant increases in the incidence of total disease/abnormalities in F1 and F3 generation male and female animals from plastics lineages. Pubertal abnormalities, testis disease, obesity, and ovarian disease (primary ovarian insufficiency and polycystic ovaries) were increased in the F3 generation animals. Kidney and prostate disease were only observed in the direct fetally exposed F1 generation plastic lineage animals. Analysis of the plastics lineage F3 generation sperm epigenome previously identified 197 differential DNA methylation regions (DMR) in gene promoters, termed epimutations. A number of these transgenerational DMR form a unique direct connection gene network and have previously been shown to correlate with the pathologies identified. Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease. The sperm DMR provide potential epigenetic biomarkers for transgenerational disease and/or ancestral environmental exposures.
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            Fetal origins of obesity.

            The worldwide epidemic of obesity continues unabated. Obesity is notoriously difficult to treat, and, thus, prevention is critical. A new paradigm for prevention, which evolved from the notion that environmental factors in utero may influence lifelong health, has emerged in recent years. A large number of epidemiological studies have demonstrated a direct relationship between birth weight and BMI attained in later life. Although the data are limited by lack of information on potential confounders, these associations seem robust. Possible mechanisms include lasting changes in proportions of fat and lean body mass, central nervous system appetite control, and pancreatic structure and function. Additionally, lower birth weight seems to be associated with later risk for central obesity, which also confers increased cardiovascular risk. This association may be mediated through changes in the hypothalamic pituitary axis, insulin secretion and sensing, and vascular responsiveness. The combination of lower birth weight and higher attained BMI is most strongly associated with later disease risk. We are faced with the seeming paradox of increased adiposity at both ends of the birth weight spectrum-higher BMI with higher birth weight and increased central obesity with lower birth weight. Future research on molecular genetics, intrauterine growth, growth trajectories after birth, and relationships of fat and lean mass will elucidate relationships between early life experiences and later body proportions. Prevention of obesity starting in childhood is critical and can have lifelong, perhaps multigenerational, impact.
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              Endocrine disruptors: from endocrine to metabolic disruption.

              Synthetic chemicals currently used in a variety of industrial and agricultural applications are leading to widespread contamination of the environment. Even though the intended uses of pesticides, plasticizers, antimicrobials, and flame retardants are beneficial, effects on human health are a global concern. These so-called endocrine-disrupting chemicals (EDCs) can disrupt hormonal balance and result in developmental and reproductive abnormalities. New in vitro, in vivo, and epidemiological studies link human EDC exposure with obesity, metabolic syndrome, and type 2 diabetes. Here we review the main chemical compounds that may contribute to metabolic disruption. We then present their demonstrated or suggested mechanisms of action with respect to nuclear receptor signaling. Finally, we discuss the difficulties of fairly assessing the risks linked to EDC exposure, including developmental exposure, problems of high- and low-dose exposure, and the complexity of current chemical environments.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                29 January 2019
                2019
                : 10
                : 14
                Affiliations
                Program on Endocrine Disruption Strategies, Commonweal , Bolinas, CA, United States
                Author notes

                Edited by: Yann Gibert, University of Mississippi Medical Center, United States

                Reviewed by: Damasia Becu-Villalobos, Instituto de Biología y Medicina Experimental (IBYME), Argentina; Andrea Diaz-Villaseñor, National Autonomous University of Mexico, Mexico

                *Correspondence: Jerrold J. Heindel jerryheindel@ 123456gmail.com

                This article was submitted to Systems and Translational Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2019.00014
                6362096
                30761083
                32a0d39f-6e02-4051-88b9-56c5283cdfa0
                Copyright © 2019 Heindel.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 July 2018
                : 10 January 2019
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 62, Pages: 8, Words: 6161
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                endocrine disruptor,obesogen,metabolism disruptor,developmental origins of disease,obesity

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