Bioenergetic Analyses of In Vitro and In Vivo Samples to Guide Toxicological Endpoints.

Toxicology is a broad field that requires the translation of biochemical responses to xenobiotic exposures into useable information to ensure the safety of the public. Modern techniques are improving rapidly, both quantitatively and qualitatively, to provide the tools necessary to expand available toxicological datasets and refine our ability to translate that data into relevant information via bioinformatics. These new techniques can, and do, impact many of the current critical roles in toxicology, including the environmental, forensic, preclinical/clinical, and regulatory realms. One area of rapid expansion is our understanding of bioenergetics, or the study of the transformation of energy in living organisms, and new mathematical approaches are needed to interpret these large datasets. As bioenergetics are intimately involved in the regulation of how and when a cell responds to xenobiotics, monitoring these changes (i.e., metabolic fluctuations) in cells/tissues post-exposure provides an approach to define the temporal scale of pharmacodynamic responses, which can be used to guide additional toxicological techniques (e.g., "omics"). This chapter will summarize important in vitro assays and in vivo imaging techniques to take real-time measurements. Using this information, our laboratory has utilized bioenergetics to identify significant time points of pharmacodynamic relevance as well as forecast the cell's eventual fate.

Deguelin and Its Role in Chronic Diseases.

Deguelin is one of four major naturally occurring rotenoids isolated from root extracts and is best recognized as a NADH: ubiquinone oxidoreductase (complex I) inhibitor, resulting in significant alterations in mitochondrial function. Deguelin has also been implicated as a regulator of apoptosis through signaling pathways, such as the (PI3K)/Akt pathway, as well as an initiator of cell cycle arrest. Consequently, this compound has accrued great interest as a potential chemopreventive and chemotherapeutic. Additionally, deguelin exposure has been linked to Parkinson's disease (PD). PD is a neurodegenerative disorder, characterized by a substantial loss of dopaminergic neurons in the substantia nigra, as well the manifestation of symptoms such as bradykinesia, rigidity, and rest tremor. While exploring the genetic impact of PD is imperative, environmental factors, such as exposure to pesticides, herbicides, and insecticides, have also been connected to the development of PD. The etiology and pathogenesis of PD are yet to be fully understood and elucidated, but mitochondrial dysfunction is gaining recognition as a molecular hallmark of PD. In fact, deguelin has been reported to elicit PD-like symptoms (degeneration of the dopaminergic pathway) in rats administered with deguelin (6 mg/kg/day for 6 days), possibly through the inhibition of mitochondrial complex I. Further research investigating the mechanisms by which deguelin inhibits central cellular processes is essential in order to advance any prospective research addressing potential applications and risks of deguelin.

Pre-conceptional folic acid supplement use according to maternal country of birth.

BACKGROUND: Supplementation with folic acid tablets in the pre-conceptional period reduces the risk of neural tube defects (NTD). In Canada, the risk of NTD may differ across certain ethnic groups. It is not known whether pre-conceptional folic acid supplement use varies according to a woman's country of birth or her duration of residency in Canada. METHODS: We included 6349 Canadian women who gave birth between January 2005 and December 2006, and who had participated in the nationally representative Maternity Experiences Survey. Reported use of a supplement containing folic acid in the three months prior to conception was evaluated in association with maternal place of birth, categorized by nine regions of the world. Odds ratios (OR) were adjusted for maternal age, gravidity, income, education level, gestational age at first prenatal care visit, and number of years living in Canada. RESULTS: Relative to a rate of 61% among Canadian-born mothers, the adjusted OR for pre-conceptional use of supplements containing folic acid was significantly lower among those who emigrated from the Caribbean and Latin America (OR 0.46; 95% confidence interval [CI] 0.31-0.70), Northern Africa and the Middle East (OR 0.33; 95% CI 0.20-0.57), and China and the South Pacific (OR 0.55; 95% CI 0.40-0.78). CONCLUSION: Certain groups of women who are immigrants to Canada take pre-conceptional folic acid supplements at rates much lower than Canadian-born women. Interventions aimed at increasing folic acid use might focus on these women, perhaps around their time of arrival in Canada.