The world is contaminated, never to return to conditions that existed prior to the chemical revolution. Although some local remediation of contamination has occurred, at a global level this is simply not possible. A class of contaminants is known as Endocrine Disrupting Chemicals (EDC) because of their ability to perturb the body's hormone systems. Poor storage, spills, deliberate and accidental dispersal have had well-document effects on wildlife and human health. However, the field of EDC research remains highly controversial and polarized. Such compounds are now a permanent part of our environment and creating previously unknown evolutionary pressures. We must transcend traditional toxicological testing to develop new methods and perspectives if we are to anticipate and understand EDCs'impact on the future. Life in this new world is a combination of ancestral exposures due to heritable epigenetic modifications to DNA in germ cells (transgenerational), together with exposures experienced during the individual's own lifetime (body burden) that cause molecular epigenetic changes to that individual. These processes are an underappreciated force in driving evolutionary change in all species, including humans. The challenge is how to model the cumulative and progressive changes both across lifespans and within generations. We propose a unique study of multigenerational exposures to sequential environmental toxicants, each known to perturb hormones, brain and behavior. Our proposed model investigates interactions of ancestral and immediate epigenetic modifications, factors that have never been studied together. Over the course of 6 generations, we make the iconoclastic prediction that individuals will evolve in unique ways due to contemporary environmental driving forces (chemical contamination), with descendants responding differently to proximal chemical stimuli than their ancestors. To do this work, we propose to model two exposures separated by 3 generations;different EDC classes will be used at environmentally relevant levels, each with a different mode of action. Endpoints will be body weight, physiological parameters, neurobiological gene expression and molecular epigenetic assays, together with behavioral characterization of the animals in a suite of behaviors involved in social, anxiety, and cognitive function. Realistically simulating the nature of life challenges across and within generations will provide the framework for understanding and anticipating how environmental contamination will affect the evolution of all species.
Exposures of humans to EDCs are universal, and these compounds have wide-ranging effects on health and disease, including possible links to neurodevelopmental and behavioral disorders. Therefore, understanding the neurobiological consequences of transgenerational EDCs and their interactions with modern-day EDCs can inform medical interventions and prevention and guide public health policy. The rat model is highly conserved with humans and its use enables us to test the cause-and-effect relationship between EDC exposures, past and present, on neurobehavioral dysfunctions and underlying molecular, cellular, and brain metabolic mechanisms.
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