INHERITANCE OF REPRODUCTIVE DISEASE; AND
MOLECULAR AND CELLULAR CONTROL OF TESTIS AND OVARY
DEVELOPMENT AND BIOLOGY
Michael K. Skinner, Ph.D.
General interest is in mammalian reproduction and environmental epigenetics on a systems biology level. The laboratory has had a long standing research program to study gonadal development and function on a molecular, cellular and physiological level (systems biology). More recently, the ability of environmental factors to act on gonadal development has been shown to cause epigenetic transgenerational inheritance of adult onset disease and influence areas of biology such as evolution. This has now become a predominant research program in the lab.
Basic research projects involve the investigation of how different cell types in a tissue interact and communicate to regulate cellular growth and differentiation, with emphasis in the area of reproductive biology. The cells of interest and specific interactions investigated have an integral role in controlling the development of the spermatozoa and oocyte. Our observations indicate that the mesenchymal cells of both the testis and ovary produce inducer substances that alter the differentiation and function of adjacent epithelial cells. The role that reproductive hormones (e.g. steroids) and growth factors (e.g. transforming growth factors, neurotropins) have in regulating these mesenchymal-epithelial cell interactions is under investigation. How these factors promote the transcriptional regulation of cellular differentiation is being investigated through an analysis of the role of a unique class of transcription factors, basic-helix-loop-helix (bHLH) factors. Information obtained from these studies is necessary before novel therapeutic agents can be designed and targeted at reproductive cells for the prevention of infertility or to act as contraceptives. The research is designed to understand testis and ovary development and function on a systems biology level.
Recently we have found that environmental toxicants (i.e. endocrine disruptors) have the ability to modify local cell-cell interactions in the testis and ovary during fetal development that influences epigenetic programming of the germline. If gestating mothers are exposed to endocrine disruptors at the time of fetal gonadal sex determination, a sub-fertility phenotype is observed in the adult male. Interestingly this phenotype is transgenerational, such that what your pregnant great grandmother was exposed to may cause disease in you with no subsequent exposure. This has been termed epigenetic transgenerational inheritance. An epigenetic effect on the programming of the male germ-line was observed and is the causal factor in this epigenetic transgenerational effect of endocrine disruptors. In addition to effects on reproduction, numerous other adult onset disease sates are observed including cancer, prostate disease, kidney disease, immune abnormalities and behavior effects. Further characterization of this phenomena and its impact on disease etiology and evolutionary biology is in progress. Further information is available at www.skinner.wsu.edu.
SKINNER LABORATORY WEBSITE: www.skinner.wsu.edu
Selected References Past Five Years
Skinner MK, Anway MD, Savenkova M, Gore A, Crews D, (2008) Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior: Environment-genome interactions. PLoS ONE 2008;3(11):e3745.
Hahn KL, Beres BJ, Rowton MJ, Skinner MK, Chang Y, Rawls A, and J Wilson-Rawls (2009) A deficiency of lunatic fringe is associated with cystic dilation of the rete testis. Reproduction. 137(1):79-93.
Nilsson EE and Skinner MK (2009) Progesterone regulation of primordial follicle assembly in bovine fetal ovaries. Molecular and Cellular Endocrinology. 313 (2009) 9–16.
Nilsson EE, Dole G and Skinner MK (2009) Neurotrophin NT-3 promotes ovarian primordial to primary follicle transition. Reproduction 138(4):697-707.
Guerrero-Bosagna C, Skinner MK (2009) Epigenetic transgenerational effects of endocrine disruptors on male reproduction. Seminars in Reproductive Medicine 27(5):403-8.
Skinner MK, Guerrero-Bosagna C (2009) Environmental signals and transgenerational epigenetics. Epigenomics 1(1), 111–117
Michael K. Skinner, Eric E. Nilsson and Ramji K. Bhandari (2009) Cell-cell signaling in the testis and ovary. In Ralph A. Bradshaw and Edward A. Dennis, editors: Handbook of Cell Signaling 2nd edition, Oxford: Academic Press, 2009, pp. 2663-2678.
Skinner MK, Manikkam M, Guerrero-Bosagna C. (2010) Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab. 21(4):214-22.
Z. Hochberg, C Junien, J-C Carel, P Boileau, C Deal, R Feil, M Fraga, M Constancia, Y Le Bouc, K Lillycrop, R Scharfmann, A Sheppard, M Skinner, M Szyf, R Waterland, DJ Waxman, E Whitelaw, K Ong, K Albertsson-Wikland (2011) Child health, developmental plasticity, epigenetics and programming. Endocrine Reviews 32(2):159-224.
Clement T, Savenkova M, Settles M, Anway M and Skinner MK (2010) Alteration of the developing testis transcriptome following embryonic vinclozolin exposure. Reprod Toxicol. 30(3):353-64.
Nilsson EE, Savenkova MI, Schindler R, Zhang B, Schadt EE and Skinner MK (2010) Gene bionetwork analysis of ovarian primordial follicle development. PLoS ONE 16;5(7):e11637.
Guerrero-Bosagna C, Settles M, Lucker BJ and Skinner MK (2010) Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS ONE 30;5(9).
Schindler R, Nilsson EE and Skinner MK (2010) Induction of ovarian primordial follicle assembly by connective tissue growth factor CTGF. PLoS ONE. 24;5(9):e12979.
Guerrero-Bosagna C & Skinner MK (2010) Transgenerational epigenetic actions of environmental compounds. Animal Reproduction. 7(3): 165-167.
Michael K Skinner (2010) Metabolic Disorders: Fathers’ nutritional legacy. Nature. 2010 Oct 21;467(7318):922-3.
Michael K. Skinner (2010) Epigenetic Transgenerational Toxicology. In: Comprehensive Toxicology, Chapter 12.07. Editor Tom Knudson. Publisher Elsevier, pgs. 89-93.
Skinner MK, Manikkam M, Guerrero-Bosagna C. (2011) Epigenetic transgenerational actions of endocrine disruptors. Reprod Toxicol. 31(3):337-43.
Michael K. Skinner (2011) Role of Epigenetics in Developmental Biology and Transgenerational Inheritance. Birth Defects. Res C, Embryo Today. 93(1):51-5.
Clement T, Bhandari R, Sadler-Riggleman I, Skinner MK (2011) Sry directly regulates the neurotrophin-3 promoter during male sex determination and testis development. Biology of Reproduction 85, 277–284.
Michael K. Skinner (2011) Environmental Epigenomics and Disease Susceptibility. EMBO Rep. 2011 Jul 1;12(7):620-2.
Michael K. Skinner (2011) Environmental Epigenetic Transgenerational Inheritance and Somatic Epigenetic Mitotic Stability. Epigenetics 1;6(7):838-42.
Bhandari R, Sadler-Riggleman I, Clement T and Skinner MK (2011) Basic Helix-Loop-Helix Transcription Factor TCF21 is a Downstream Target of the Male Sex Determining Gene SRY. PLoS ONE. 2011;6(5):e19935.
Nilsson EE, Schindler R, Savenkova MI and Skinner MK (2011) Inhibitory Actions of Anti-Müllerian Hormone (AMH) on Ovarian Primordial Follicle Assembly. PLoS One. 2011;6(5):e20087.
Guerrero-Bosagna C and Skinner MK (2012) Environmentally Induced Epigenetic Transgenerational Inheritance of Phenotype and Disease. Molecular and Cellular Endocrinology 6;354(1-2):3-8.
Crews D, Gillette R, Manikkam M, Savenkova M and Skinner MK (2012) Epigenetic transgenerational inheritance of altered stress responses. PNAS 5;109(23):9143-8.
Carlos Guerrero-Bosagna, Trevor R. Covert, Matthew Settles, Matthew D. Anway, and Michael K. Skinner. (2012) Epigenetic Transgenerational Inheritance of Vinclozolin Induced Mouse Adult Onset Disease and Associated Sperm Epigenome Biomarkers. Reproductive Toxicology (Conditionally Accepted).
Michael K. Skinner, Marina Savenkova, Bin Zhang, David Crews (2012) Gene Bionetworks Involved in Epigenetic Transgenerational Inheritance of Environmentally Altered Sexual Selection Behaviors: Role Epigenetics in Evolutionary Biology. (Submitted).
Eric Nilsson, Ginger Larsen, Mohan Manikkam, Carlos Guerrero-Bosagna, Marina Savenkova and Michael K. Skinner (2012) Environmentally induced epigenetic transgenerational inheritance of ovarian disease. PLoS One. 7(5):e36129.
Mohan Manikkam, Carlos Guerrero-Bosagna, Rebecca Tracey, Md. M. Haque and Michael K. Skinner (2012) Transgenerational Actions of Environmental Compounds on Reproductive Disease and Identification of Epigenetic Biomarkers of Ancestral Exposures. PLoS ONE 7(2):e31901.
Bhandari R, Haque Md, Skinner MK (2012) Global Genome Analysis of the Downstream Binding Targets of Testis Determining Factor SRY AND SOX9. PLoS ONE 7(9):e43380.
Bhandari R, Schinke E, Haque Md, Skinner MK (2012) SRY Induced TCF21 Genome-wide Targets and Cascade of bHLH Factors During Sertoli Cell Differentiation and Male Sex Determination. Biology of Reproduction (Conditionally Accepted).
Skinner MK, Manikkam M, Haque Md., Zhang B, Savenkova M (2012) Epigenetic Transgenerational Inheritance of Somatic Transcriptomes and Epigenetic Control Region. Genome Biology (In Press).
Mohan Manikkam, Rebecca Tracey, Carlos Guerrero-Bosagna & Michael K. Skinner (2012) Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Adult-Onset Disease and Sperm Epimutations. PLoS ONE (Submitted).
Rebecca Tracey, Mohan Manikkam, Carlos Guerrero-Bosagna, & Michael K. Skinner (2012) Hydrocarbon (Jet Fuel JP-8) Induces Epigenetic Transgenerational Inheritance of Adult-Onset Disease and Sperm Epimutations. Reproductive Toxicology (Submitted).
Mohan Manikkam, Rebecca Tracey, Carlos Guerrero-Bosagna, Michael K. Skinner (2012) Pesticide and Insect Repellent Mixture (Permethrin and DEET) Induces Epigenetic Transgenerational Inheritance of Disease and Sperm Epimutations. Reproductive Toxicology (In Press).
Mohan Manikkam, Rebecca Tracey, Carlos Guerrero-Bosagna, and Michael K. Skinner (2012) Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations. PLoS ONE 7(9): e46249.