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 the epigenetic transgenerational inheritance of disease and phenotypic variation which impacts areas of biology such as medicine or evolution. This has now become a predominant research program in the lab.
Basic reproductive biology 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.
Previously we have found that environmental toxicants (e.g. 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 females are exposed to environmental toxicants at the time of fetal gonadal sex determination, a number of adult onset diseases develop. 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 germ-line was observed and is the causal factor in this epigenetic transgenerational effect of environmental toxicants. In addition to effects on reproduction, numerous other adult onset disease sates are observed including cancer, prostate disease, kidney disease, obesity, 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 (2014) A New Kind of Inheritance. Scientific American 311(2)41-45.
Skinner MK, Savenkova M, Zhang B, and Crews D (2014) Gene Bionetworks Involved in Epigenetic Transgenerational Inheritance of Altered Mate Preference: Environmental Epigenetics and Evolutionary Biology. BMC Genomics 16;15(1):337.
Kabasenche WP, and Skinner MK (2014) DDT, Epigenetic Harm, and Transgenerational Environmental Justice. Environmental Health Environmental Health 2014 13:62.
Skinner, MK (2014) Environmental Stress and Epigenetic Transgenerational Inheritance. BMC Medicine 12:153.
Guerrero-Bosagna C, Skinner MK, (2014) Environmentally Induced Epigenetic Transgenerational Inheritance of Male Infertility. Curr Opin Genet Dev. 4;26C:79-88.
Guerrero-Bosagna C, and Skinner MK (2014) Environmental Epigenetics and Phytoestrogen/Phytochemical Exposures. Journal of Steroid Biochemistry & Molecular Biology 139:270– 276.
Bao J, Zhang Y, Schuster AS, Ortogero N, Nilsson EE, Skinner MK and Yan W (2014) Conditional inactivation of Miwi2 reveals that MIWI2 is only essential for prospermatogonial development in mice. Cell Death and Differentiation. 21(5):783-796.
Feeney A, Nilsson E, and Skinner MK (2014) Cytokine (IL16) and Tyrphostin Actions on Ovarian Primordial Follicle Development. Reproduction. 148(3):321-331.
Skinner MK and Guerrero-Bosagna C (2014) Role of CpG Deserts in the Epigenetic Transgenerational Inheritance of Differential DNA Methylation Regions. BMC Genomics 15:692.
Guerrero-Bosagna C, Weeks S, and Skinner MK (2014) Identification of Genomic Features in Environmentally Induced Epigenetic Transgenerational Inherited Sperm Epimutations. PLoS ONE 17;9(6):e100194.
Skinner MK, Guerrero-Bosagna C, Haque M, Knutie S, Koop J, and Clayton D (2014) Epigenetics and the Speciation and Evolution of Darwin’s Finches. Genome Biology & Evolution 24;6(8):1972-89.
Haque M, Skinner MK and Holder LB (2014) Imbalanced Class Learning in Epigenetics. J Comput Biol. 21(7):492-507.
Nilsson E, Larsen G, and Skinner MK (2014) Roles of Gremlin1 and Gremlin2 in Regulating Ovarian Primordial to Primary Follicle Transition. Reproduction. 147(6):865-74.
Nilsson E and Skinner MK (2014) Environmentally Induced Epigenetic Transgenerational Inheritance of Disease Susceptibility. Translational Research. S1931-5244(14)00077-2.
Manikkam M, Haque M, Guerrero-Bosagna C, Nilsson EE, Skinner MK (2014) Pesticide methoxychlor promotes the epigenetic transgenerational inheritance of adult onset disease and sperm epimutations through the female germline. PLoS ONE 9(7)e102091.
Manikkam M, Tracey R, Guerrero-Bosagna C, and Skinner MK (2013) Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Adult-Onset Disease and Sperm Epimutations. PLoS ONE 8(1):e55387.
Tracey R, Manikkam M, Guerrero-Bosagna C, and Skinner MK (2013) Hydrocarbon (Jet Fuel JP-8) Induces Epigenetic Transgenerational Inheritance of Adult-Onset Disease and Sperm Epimutations. Reproductive Toxicology. 36:104-116.
Hope BT, Skinner MK, Kenny PJ, Akbarian S. (2013) Exploring the epigenetics of cocaine resistance. Nat Med. 19(2):136-7.
Skinner MK, Manikkam M, Tracey R, Nilsson E, Haque Md. M, and Guerrero-Bosagna C (2013) Ancestral DDT Exposure Promotes Epigenetic Transgenerational Inheritance of Obesity. BMC Medicine 11:228.
Guerrero-Bosagna C and Skinner MK (2013) Environmental Epigenetics and Effects on Male Fertility. In: Damage in the Genetic Material of Human Spermatozoa: Relation to Fertility. Springer. Adv Exp Med Biol. 2014;791:67-81.
Guerrero-Bosagna C, Savenkova M, Haque Md. M, Sadler-Riggleman I, and Skinner MK (2013) Environmentally Induced Epigenetic Transgenerational Inheritance of Altered Sertoli Cell Transcriptome and Epigenome: Molecular Etiology of Male Infertility. PLoS ONE 8(3): e59922.
Skinner MK, Guerrero-Bosagna C, Haque Md, Nilsson E, Bhandari R, and McCarrey J (2013) Environmentally Induced Transgenerational Epigenetic Reprogramming of Primordial Germ Cells and Subsequent Germline. PLoS ONE 15;8(7):e66318.
Haque Md, Holder LB, Skinner MK, Cook DJ (2013) Generalized Query Based Active Learning to Identify Differentially Methylated Regions in DNA. IEEE/ACM Trans Comput Biol Bioinform 10(3):632-44.
Nilsson E, Zhang B, and Skinner MK (2013) Gene Bionetworks that Regulate Ovarian Primordial Follicle Assembly. BMC Genomics 14:496.
Skinner MK (2013) Environmental Epigenetics and Epigenetic Transgenerational Inheritance. In: Epigenetics and Human Health. Editors: Randy L Jirtle, Frederick L. Tyson. Springer. 2013, pp. 245-256.
Skinner MK (2013) Environmentally Induced Epigenetic Transgenerational Inheritance of Disease. In Ten Critical Topics in Reproductive Medicine, S. Sanders, Ed. (Science/AAAS, Washington, DC), pp. 18-20.
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.
Guerrero-Bosagna C, Covert TR, Settles M, Anway MD, and Skinner MK. (2012) Epigenetic Transgenerational Inheritance of Vinclozolin Induced Mouse Adult Onset Disease and Associated Sperm Epigenome Biomarkers. Reproductive Toxicology 34(4):694-707.
Nilsson E, Larsen G, Manikkam M, Guerrero-Bosagna C, Savenkova M and Skinner MK (2012) Environmentally induced epigenetic transgenerational inheritance of ovarian disease. PLoS One. 7(5):e36129.
Manikkam M, Guerrero-Bosagna C, Tracey R, Haque M, and Skinner MK (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 6;87(6):131.
Skinner MK, Manikkam M, Haque Md., Zhang B, Savenkova M (2012) Epigenetic Transgenerational Inheritance of Somatic Transcriptomes and Epigenetic Control Region. Genome Biology 3;13(10):R91.
Manikkam M, Tracey R, Guerrero-Bosagna C, and Skinner MK (2012) Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations. PLoS ONE 7(9): e46249.
Manikkam M, Tracey R, Guerrero-Bosagna C, and Skinner MK (2012) Pesticide and Insect Repellent Mixture (Permethrin and DEET) Induces Epigenetic Transgenerational Inheritance of Disease and Sperm Epimutations. Reproductive Toxicology 34(4):708-19.
Skinner MK, Manikkam M, Guerrero-Bosagna C. (2011) Epigenetic transgenerational actions of endocrine disruptors. Reprod Toxicol. 31(3):337-43.
Skinner MK (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.
Skinner MK (2011) Environmental Epigenomics and Disease Susceptibility. EMBO Rep. 2011 Jul 1;12(7):620-2.
Skinner MK (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.
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.
Skinner MK, Manikkam M, Guerrero-Bosagna C. (2010) Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab. 21(4):214-22.
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.
Skinner MK (2010) Metabolic Disorders: Fathers’ nutritional legacy. Nature. 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.
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.