Ancestral perinatal obesogen exposure results in a transgenerational thrifty phenotype in mice

Self Cite

Obesity and associated disorders are now a global pandemic. The prevailing clinical model for obesity is overconsumption of calorie‐dense food and diminished physical activity (the calories in—calories out model). However, this explanation does not account for numerous recent research findings demonstrating that a variety of environmental factors can be superimposed on diet and exercise to influence the development of obesity. The environmental obesogen model proposes that exposure to chemical obesogens during in utero and/or early life can strongly influence later predisposition to obesity. Obesogens are chemicals that inappropriately stimulate adipogenesis and fat storage, in vivo either directly or indirectly. Numerous obesogens have been identified in recent years and some of these elicit transgenerational effects on obesity as well as a variety of health end‐points after exposure of pregnant F0 females. Prenatal exposure to environmental obesogens can produce lasting effects on the exposed animals and their offspring to at least the F4 generation. Recent results show that some of these transgenerational effects of obesogen exposure can be carried across the generations via alterations in chromatin structure and accessibility. That some chemicals can have permanent effects on the offspring of exposed animals suggests increased caution in the debate about whether and to what extent exposure to endocrine‐disrupting chemicals and obesogens should be regulated.

Section: The Obesogen Hypothesismentioning

confidence: 99%

Section: Modulate Metabolic Set Points?mentioning

confidence: 99%

Section: Modulate Metabolic Set Points?mentioning

confidence: 99%

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Transgenerational effects of obesogens

Lee

Blumberg

2019

Self Cite

“…These effects led to a more significant decline in basal metabolic rate during weight loss and less increase in basal metabolic rate during weight regain. Chamorro-Garcia et al 39 showed that ancestral exposure to tributyltin resulted in animals (four generations later) that were more sensitive to gaining weight when they were switched to a high-fat diet compared to control animals. When these animals were returned to a standard control diet, they lost weight more slowly than control animals.…”

Section: F I G U R E 2 Transgenerationalmentioning

confidence: 99%

The developmental basis of disease: Update on environmental exposures and animal models

Heindel

2018

At the Prenatal Programming and Toxicity (PPTox) Conference I in 2008, I presented an overview of the developmental origins of health and disease field focusing on environmental chemical exposures and disease outcomes. At that time, I noted that the field was getting off the ground with a focus on developmental exposure to a small number of endocrine disrupting chemicals (EDCs) and disease outcomes across the lifespan in animal models. In this update, I note that the DOHaD field has changed significantly over the last decade. There are new windows of susceptibility including preconception, prepuberty, a focus on the mother and not just the offspring, and a significant focus on the new field of epigenetic transgenerational inheritance. New disease focus areas have sprung up including obesity, type 2 diabetes and fatty liver disease, all with a connection to developmental exposures to EDCs. There is also a focus on the study of new EDCs, molecular mechanisms, the development of new biomarkers of exposure and disease outcomes and studies focusing on intervention and prevention studies.

“…51 Thus, a recent study, presented at PPTOX VI, showed that transgenerational inheritance of obesity was observed from perinatal tributyltin exposure, apparently mediated through altered higher-order chromatin organization. 52 Reorganized chromatin, transmissible through meiosis and mitosis, can in turn influence DNA methylation at accessible sites that modified transcription, suggesting that this is a proximal event. These new mechanistic insights indicate that a revision of research paradigms and interpretation is required.…”

Section: Mechanistic Insightsmentioning

confidence: 99%

Timescales of developmental toxicity impacting on research and needs for intervention

Grandjean

Abdennebi-Najar

Barouki

et al. 2018

Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision-making must be weighed against the costs and necessary duration of research, as well as the long-term costs to human health because of delayed protection of vulnerable early-life stages of human development and, possibly, future generations. Although two-generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY-BPA-type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity (PPTOX) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.