PH.D. The University of Western Ontario
B.Sc. The University of Waterloo
Office: Dental Science Building, Room 2023
The Susan Vitali-Lovell Laboratory for Studies in
Fetal Programming of Human Health Risks
p. 519.661.2111 x. 84238
See Publications by Daniel Hardy on PubMed
The main focus of my laboratory is investigating the role of nuclear receptors in fetal programming. While emerging epidemiological evidence suggests that the risks of adult onset diseases are inversely related to birth weight, very little is known about the genetic and/or epigenetic changes which underlie these alterations in fetal and postnatal development. Numerous animals models including maternal caloric and/or nutrient restriction, along with chemically induced gestational diabetes, hypoxia, LPS-invoked inflammation, glucocorticoid exposure, and decreased dietary protein have broadened our understanding how in utero insults may lead to restricted fetal growth. However, understanding the overall role of transcription factors involved in mediating these developmental abnormalities would provide us with better strategies in preventing the onset of adult diseases in mammals.
Nuclear receptors represent the largest family of transcription factors found in metazoans, binding to steroid hormones, fat-soluble vitamins, along with oxysterols and bile acids from the diet. Although the roles of many nuclear receptors are well defined, very little is known about their function in fetal programming, which leads to permanent changes in physiological and/or metabolic processes in adulthood. In my laboratory, we use 'candidate transcription factor' approaches to examine the roles of lipid-sensing nuclear receptors in various models of fetal programming. One such model includes maternal protein restriction, which leads to lower birth weight, impaired offspring growth, decreased liver to body ratio, and an increase in fetal liver cholesterol concentrations.
To address the molecular mechanisms underlying these ‘programmed' changes in nuclear receptor binding and downstream target genes, we employ chromatin immunoprecipitation (ChIP) in tissues and in cells to examine the in vivo binding of nuclear receptors to their respective promoters throughout fetal development. This helps us identify the crucial subset of lipid-sensing nuclear receptors underlying these fetal programming events. Moreover, the use of ChIP in vivo and in vitro further enhances our understanding of how epigenetic modifications are involved in the coordinated control of gene transcription during normal and abnormal fetal development.
Ma N, Nicholson CJ, Wong M, Holloway AC, and DB Hardy. (2014) Fetal and Neonatal Exposure to Nicotine Leads to Augmented Hepatic and Circulating Triglycerides in Adult Male Offspring Due to Increased Expression of Fatty Acid Synthase, Toxicology and Applied Pharmacology 275:1-11.
Sohi G, Barry EJ, Velonosi TJ, Urquhart BL, and DB Hardy. (2014) Nutritional Mismatch in Postnatal Life of Low Birth Weight Rat Offspring Leads to Elevated Hepatic Cyp3A and Cyp2C Activity in Adulthood, Drug Metabolism and Disposition 42:221-228.
Osumek JE, Revesz A, Morton JS, Davidge ST, and DB Hardy. (2014) Enhanced trimethylation of histone H3 mediates impaired expression of hepatic glucose-6-phosphatase (G6Pase) expression in offspring from rat dams exposed to hypoxia during pregnancy, Reproductive Sciences 21(1):112-121.
Vo T, Revesz A, Sohi G, Ma N, and DB Hardy. (2013) Maternal protein restriction leads to disruption of hepatic gluconeogenic gene expression in adult male offspring due to impaired expression of the liver X receptor, J. of Endocrinology, Jun 1;218(1):85-97.
Sohi G, Revesz A, and DB Hardy. (2013) Nutritional Mismatch in Postnatal Life of Low Birth Weight Rat Offspring Leads to Increased Phosphorylation of Hepatic Eukaryotic Initiation Factor 2α in Adulthood, Metabolism 62:1367-1374.
Sohi G, Marchand K, Revesz A, Arany E, and DB Hardy (2011) Maternal Protein Restriction Elevates Cholesterol in Adult Rat Offspring Due to Repressive Changes in Histone Modifications at the Cholesterol 7α-Hydroxylase Promoter, Molecular Endocrinology. 25(5): 785-797