Low level exposure to PBDEs: testing the hormetic and epigenetic hypotheses
Principal Investigator: Lucio G Costa
Abstract: DESCRIPTION (provided by applicant): Polybrominated diphenyl ethers (PBDEs) are an important group of flame retardants, which have been widely used in a variety of consumer products. As they leach out into the environment, PBDEs have become persistent organic pollutants, and have also been detected in human blood and breast milk. Body burden of PBDEs in humans in North America is much higher than in the rest of the world, and it is highest in infants (because of exposure through breast milk) and in toddlers (because of exposure through house dust and the diet). This has raised concerns for the potential developmental toxicity and neurotoxicity of PBDEs, as animal studies have shown that exposure during the prenatal and/or postnatal periods causes long-lasting behavioral abnormalities, particularly in the domains of motor activity and cognition. Limited evidence is also suggestive of possible developmental adverse effects in humans from PBDE exposure. The mechanisms of PBDE developmental neurotoxicity are still elusive, but include potential effects on thyroid hormone homeostasis and direct effects on brain cells, particularly oxidative stress- mediated toxicity. Most mechanistic studies with PBDEs have utilized micromolar concentrations of these compounds, though levels of PBDEs in adults in the USA are in the nanomolar range. Investigations of the biological effects of low, environmentally relevant, concentrations of PBDEs, are the focus of proposed studies. The first hypothesis is that chronic exposure of mouse neurons in vitro to low concentrations of BDE-47 (chosen as a model congener) would not cause any overt toxicity in cells, but would act in a hormetic (pre-conditioning) fashion. A lo level of oxidative stress caused by BDE-47 would stimulate defense mechanisms in the cell, which would protect them from the toxicity of higher exposures. However, gene-environment interactions would play a role in such hormetic response. Indeed, we hypothesize that the hormetic response would be lost in cells from mice mimicking human polymorphisms of Gclm (glutamate cysteine ligase modifier subunit) i.e. Gclm+/- and Gclm-/- mice). The second hypothesis is that exposure of neurons in vitro to low levels of BDE-47 would result in epigenetic changes, at the level of DNA methylation and of miRNA homeostasis, which may be relevant for brain development and may result in specific changes in gene expression. Altogether, results from this R21 proposal will provide the basis for further in vivo studies to be carried out with lo doses PBDEs.
Funding Period: 2013-05-15 - 2015-04-30
more information: NIH RePORT
- A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicityLucio G Costa
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA Department of Neuroscience, University of Parma, Parma, Italy Electronic address
Toxicol Lett 230:282-94. 2014....
- EPIDEMIOLOGY OF ALCOHOL PROBLEMSThomas K Greenfield; Fiscal Year: 2013..We plan to build research capacity in the Center and other organizations, enhance careers of new investigators, and make key findings accessible to researchers, policy makers, practitioners, and the public. ..
- Prenatal stress: the epigenetic basis of maternal and perinatal effectsBenjamin Tycko; Fiscal Year: 2013....
- Elucidating Risks: From Exposure and Mechanism to OutcomeJames A Swenberg; Fiscal Year: 2013..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
- Puerto Rico Testsite for Exploring Contamination Threats (PRoTECT)Akram N Alshawabkeh; Fiscal Year: 2013..The cross-disciplinary approach will employ the data-rich centralized data repository and integrated modeling/analysis capabilities to better understand complex interrelationships between multiple risk factors. ..
- BIOMARKERS OF EXPOSURE TO HAZARDOUS SUBSTANCESBruce D Hammock; Fiscal Year: 2013..abstract_text> ..
- Semi-volatile PCBs: Sources, Exposures, ToxicitiesLarry W Robertson; Fiscal Year: 2013..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
- Beryllium: Exposure Immune and Genetic MechanismsLee S Newman; Fiscal Year: 2013..The productivity and continuance demonstrate quality, commitment and ability to work together. PROGRAM AS INTERGRATED EFFORT ..
- Longitudinal study of exposure to PBDEs and PFCs and child neurobehaviorKimberly Yolton; Fiscal Year: 2013..This research is closely related to the NIH mission to investigate prevalent environmental toxicants and children's neurodevelopment. ..
- IRS insecticides for malaria control and child neurodevelopment in South AfricaBrenda Eskenazi; Fiscal Year: 2013..This study aims to provide data to evaluate the risk/benefit of different methods of malaria control and for the development of appropriate interventions to reduce exposure to pregnant women and children. ..