Endocrine and Metabolic Disruption
Environmental endocrine disrupting compounds (EDCs) are hormonally active, synthetic or natural compounds that interfere with the normal functioning of the endocrine system (Damstra et al., 2002). Exposure to EDCs continues to be a significant and contentious public health issue (Gierthy, 2002). The mechanisms of action of EDCs are diverse, and include estrogenic, anti-androgenic and anti-oxidant actions, inhibition of cell cycles and differentiation, modulation of angiogenesis, and substantive changes in the expression or activity of steroidogenic enzymes (Whitehead and Rice, 2006). The endocrine and reproductive effects of these chemicals are believed to be due to their ability to act as agonists or antagonists of endogenous hormones. Classically, EDCs have been viewed as exerting their effects exclusively by genomic mechanisms, acting as exogenous steroid mimics by binding to the receptor. Recently, it has been found that EDCs can also act via non-genomic and epigenetic mechanisms (Waring and Harris, 2005). It is concerning that the developing fetus and neonates appear to be especially susceptible to EDC exposure resulting in adaptations and organizational changes that appear to predispose them to later dysfunctions. Most effects of prenatal exposure to EDCs appear to be irreversible and some may be transgenerational (Anway et al., 2000). Exposure to several EDCs is chronic, their effects may be latent, and there may be no “lowest” dose that is without adverse consequences (Crews et al., 2000). EDCs in the environment rarely exist in isolation, and may act synergistically rather than additively with other EDCs (Crews et al., 2000).
- Leader: Vasantha Padmanabhan, PhD
Genomic and Epigenomic Mechanisms
Epigenetic mechanisms are essential regulators of gene expression throughout life, and include methylation of DNA and methylation, acetylation, phosphorylation, ubiquitination and polyADP-ribosylation of histones. These covalent modifications regulate chromatin structure, chromatin remodeling, genome stability and DNA repair, with an ultimate impact on gene expression and cellular function (Richardson, 2007; Shukia et al., 2008). Epigenetic modifications are dynamic and susceptible to environmental influences. DNA methylation patterns must be replicated each time a cell divides, and the efficiency of this reaction depends on intracellular S-adenosylmethionine, S-adenosylhomocysteine, and DNA methyltransferase 1 levels (Richardson, 2007). Thus the replication of DNA methylation patterns is sensitive to dietary influences and xenobiotics that inhibit DNA methylation, such as genistein and bisphenol A (Baccarelli and Bollati, 2009). Hypermethylation of DNA sequences also occurs with aging, contributing to the development of malignancies (Cheung et al., 2009), and is likely environmentally sensitive. Histone modifications are sensitive to environmental agents through impacts on the histone deacetylases and acetylases or the intracellular pools of molecules required for the modifications, such as acetyl-CoA or S-adenosylmethionine. Epigenetic dysregulation may contribute to the development of many poorly understood human diseases, such as asthma (Miller and Ho, 2008), prematurity (Hofman et al., 2006), metabolic syndrome (Symonds et al., 2009) and neurodegenerative diseases such as Alzheimer’s (Zawia et al., 2009), as well as cancers, lupus, and other diseases (Dolinoy and Jirtle, 2008).
- Leader: Dana C. Dolinoy, PhD
Oxidative Stress and Inflammation
Oxidative stress has a central role in many toxicant-induced responses. Cells continuously generate reactive molecular species through toxicant actions as well as through normal cellular respiration and metabolism. Reactive oxygen species (ROS) can oxidize cell membrane lipids, proteins and nucleic acids, and when these pro-oxidant reactions exceed cellular homeostatic capacity, oxidative stress ensues. Oxidative stress has been implicated in a wide variety of pathological processes, including asthma, neurodegenerative disease, metabolic syndrome, autoimmune disorders, cancer, diabetes, obesity, and more recently, preterm birth. The objective of this research team is to provide a more complete understanding of the role of ROS-mediated biological responses in environmentally-relevant diseases.
- Leader: Toby Lewis, MD, MPH