Sex in basic research: Concepts in the cardiovascular field

Cardiovascular Research

Volumn 113, Issue 7, 2017, Pages 711-724

  Ventura Clapier, Renée ^a   Dworatzek, Elke ^b   Seeland, Ute ^b   Kararigas, Georgios ^b   Arnal, Jean Francois ^c   Brunelleschi, Sandra ^d   Carpenter, Thomas C ^e   Erdmann, Jeanette ^b,f   Franconi, Flavia ^g   Giannetta, Elisa ^h   Glezerman, Marek ⁱ   Hofmann, Susanna M ^j,k,l   Junien, Claudine ^m   Katai, Miyuki ⁿ   Kublickiene, Karolina ^o   König, Inke R ^b,f   Majdic, Gregor ^p   Malorni, Walter ^q   Mieth, Christin ^b,r   Miller, Virginia M ^s   Reynolds, Rebecca M ^t   Shimokawa, Hiroaki ^u   Tannenbaum, Cara ^v   D’Ursi, Anna Maria ^w   Regitz Zagrosek, Vera ^b   more..

^a Universite Paris Sud   (France)

^b DZHK GERMAN CENTRE FOR CARDIOVASCULAR RESEARCH   (Germany)

^c UNIVERSITÉ PAUL SABATIER   (France)

^d UNIVERSITY OF EASTERN PIEDMONT   (Italy)

^e UNIVERSITY OF EDINBURGH   (United Kingdom)

^f UNIVERSITY OF LÜBECK   (Germany)

^g UNIVERSITY OF SASSARI   (Italy)

^h SAPIENZA UNIVERSITY OF ROME   (Italy)

ⁱ TEL AVIV UNIVERSITY   (Israel)

^j LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^k INSTITUTE OF EPIDEMIOLOGY   (Germany)

^l GERMAN CENTER FOR DIABETES RESEARCH DZD   (Germany)

^m INRA Institut National de la Recherche Agronomique   (France)

ⁿ TOKYO WOMEN'S MEDICAL UNIVERSITY   (Japan)

^o KAROLINSKA INSTITUTE   (Sweden)

^p UNIVERSITY OF LJUBLJANA   (Slovenia)

^q ISTITUTO SUPERIORE DI SANITÀ   (Italy)

^r MAX DELBRÜCK CENTER FOR MOLECULAR MEDICINE   (Germany)

^s MAYO CLINIC   (United States)

^t UNIVERSITY OF EDINBURGH   (United Kingdom)

^u TOHOKU UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^v CANADIAN INSTITUTES OF HEALTH RESEARCH   (Canada)

^w UNIVERSITY OF SALERNO   (Italy)

more..

Author keywords

Animal models; Basic research; Cardiac cell models; Chromosomes; Hormones; Sex

Indexed keywords

ESTROGEN RECEPTOR; GLUCOSE; LIPID; PHOSPHODIESTERASE V INHIBITOR; SEX HORMONE; TESTOSTERONE;

BASIC RESEARCH; BRAIN; CANADA; CARDIAC MUSCLE; CARDIOVASCULAR DISEASE; CELL DEATH; CELL SURVIVAL; DISEASE COURSE; DRUG DEVELOPMENT; EPIGENETICS; GENE CONTROL; GENOME-WIDE ASSOCIATION STUDY; GLUCOSE METABOLISM; HEART FUNCTION; HUMAN; HYPOTHALAMUS HYPOPHYSIS ADRENAL SYSTEM; IN VIVO STUDY; JAPAN; LIPID METABOLISM; MEDICAL RESEARCH; MITOCHONDRION; NONHUMAN; PRECLINICAL STUDY; PREGNANCY COMPLICATION; PRIMARY CELL; PRIORITY JOURNAL; PROTEIN STRUCTURE; PROTEOMICS; REVIEW; SEX CHROMOSOME; SEX DIFFERENCE; TRANSCRIPTOMICS; UNITED STATES; X CHROMOSOME; ANIMAL; CARDIOVASCULAR SYSTEM; FEMALE; GENETIC PREDISPOSITION; GENETICS; HEALTH CARE DISPARITY; HEALTH DISPARITY; MALE; METABOLISM; METHODOLOGY; PATHOPHYSIOLOGY; PHENOTYPE; PREGNANCY; PROCEDURES; PROGNOSIS; RISK FACTOR; SEX FACTOR; SEXUAL CHARACTERISTICS; Y CHROMOSOME;

ANIMALS; BIOMEDICAL RESEARCH; CARDIOVASCULAR DISEASES; CARDIOVASCULAR SYSTEM; CHROMOSOMES, HUMAN, X; CHROMOSOMES, HUMAN, Y; FEMALE; GENETIC PREDISPOSITION TO DISEASE; GONADAL STEROID HORMONES; HEALTH STATUS DISPARITIES; HEALTHCARE DISPARITIES; HUMANS; MALE; PHENOTYPE; PREGNANCY; PROGNOSIS; RESEARCH DESIGN; RISK FACTORS; SEX CHARACTERISTICS; SEX FACTORS;

EID: 85027309513     PISSN: 00086363     EISSN: 17553245     Source Type: Journal    
DOI: 10.1093/cvr/cvx066     Document Type: Review

References (87)

1. Beery AK, Zucker I. Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 2011;35:565–572.
2. Richardson SS, Reiches M, Shattuck-Heidorn H, Labonte ML, Consoli T. Opinion: focus on preclinical sex differences will not address women’s and men’s health disparities. Proc Natl Acad Sci U S A 2015;112:13419–13420.
3. Eugenmed Cardiovascular Clinical Study Group, Regitz-Zagrosek V, Oertelt-Prigione S, Prescott E, Franconi F, Gerdts E, Foryst-Ludwig A, Maas AH, Kautzky-Willer A, Knappe-Wegner D, Kintscher U, Ladwig KH, Schenck-Gustafsson K, Stangl V. Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes. Eur Heart J 2016;37:24–34.
4. Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev 2017;97:1–37.
5. Blenck CL, Harvey PA, Reckelhoff JF, Leinwand LA. The importance of biological sex and estrogen in rodent models of cardiovascular health and disease. Circ Res 2016;118:1294–1312.
6. Mcgregor AJ, Hasnain M, Sandberg K, Morrison MF, Berlin M, Trott J. How to study the impact of sex and gender in medical research: a review of resources. Biol Sex Differ 2016;7:46.
7. Oertelt-Prigione S, Gohlke BO, Dunkel M, Preissner R, Regitz-Zagrosek V. GenderMedDB: an interactive database of sex and gender-specific medical literature. Biol Sex Differ 2014;5:7.
8. Berletch JB, Yang F, Xu J, Carrel L, Disteche CM. Genes that escape from X inactivation. Hum Genet 2011;130:237–245.
9. Hochberg Z, Feil R, Constancia M, Fraga M, Junien C, Carel JC, Boileau P, Le Bouc Y, Deal CL, Lillycrop K, Scharfmann R, Sheppard A, Skinner M, Szyf M, Waterland RA, Waxman DJ, Whitelaw E, Ong K, Albertsson-Wikland K. Child health, developmental plasticity, and epigenetic programming. Endocr Rev 2011;32:159–224.
10. Kuroki S, Matoba S, Akiyoshi M, Matsumura Y, Miyachi H, Mise N, Abe K, Ogura A, Wilhelm D, Koopman P, Nozaki M, Kanai Y, Shinkai Y, Tachibana M. Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science 2013;341:1106–1109.
11. Reynolds RM. Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis–2012 Curt Richter Award Winner. Psychoneuroendocrinology 2013;38:1–11.
12. Carpenter T, Grecian S, Reynolds R. Sex differences in early life programming of the hypothalamic-pituitary-adrenal axis in humans suggest increased vulnerability in females: a systematic review. J Dev Orig Health Dis 2017;8:244–255.
13. Majdic G, Tobet S. Cooperation of sex chromosomal genes and endocrine influences for hypothalamic sexual differentiation. Front Neuroendocrinol 2011;32:137–145.
14. Mccarthy MM, Nugent BM. At the frontier of epigenetics of brain sex differences. Front Behav Neurosci 2015;9:221.
15. Nugent BM, Wright CL, Shetty AC, Hodes GE, Lenz KM, Mahurkar A, Russo SJ, Devine SE, Mccarthy MM. Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci 2015;18:690–697.
16. Hindorff L, Macarthur J, Morales J, Junkins H, Hall P. A Catalog of Published Genome-wide Association Studies. 2013. Available at: http://www.genome.gov/gwastudies/.
17. Konig IR, Loley C, Erdmann J, Ziegler A. How to include chromosome X in your genome-wide association study. Genet Epidemiol 2014;38:97–103.
18. Delaval K, Govin J, Cerqueira F, Rousseaux S, Khochbin S, Feil R. Differential histone modifications mark mouse imprinting control regions during spermatogenesis. EMBO J 2007;26:720–729.
19. Li E, Beard C, Jaenisch R. Role for DNA methylation in genomic imprinting. Nature 1993;366:362–365.
20. Augui S, Nora EP, Heard E. Regulation of X-chromosome inactivation by the X-inactivation centre. Nat Rev Genet 2011;12:429–442.
21. Penaloza CG, Estevez B, Han DM, Norouzi M, Lockshin RA, Zakeri Z. Sex-dependent regulation of cytochrome P450 family members Cyp1a1, Cyp2e1, and Cyp7b1 by methylation of DNA. FASEB J 2014;28:966–977.
22. Kararigas G, Bito V, Tinel H, Becher E, Baczko I, Knosalla C, Albrecht-Kupper B, Sipido KR, Regitz-Zagrosek V. Transcriptome characterization of estrogen-treated human myocardium identifies myosin regulatory light chain interacting protein as a sex-specific element influencing contractile function. J Am Coll Cardiol 2012;59:410–417.
23. Kararigas G, Dworatzek E, Petrov G, Summer H, Schulze TM, Baczko I, Knosalla C, Golz S, Hetzer R, Regitz-Zagrosek V. Sex-dependent regulation of fibrosis and inflammation in human left ventricular remodelling under pressure overload. Eur J Heart Fail 2014;16:1160–1167.
24. Heidecker B, Lamirault G, Kasper EK, Wittstein IS, Champion HC, Breton E, Russell SD, Hall J, Kittleson MM, Baughman KL, Hare JM. The gene expression profile of patients with new-onset heart failure reveals important gender-specific differences. Eur Heart J 2010;31:1188–1196.
25. Isensee J, Witt H, Pregla R, Hetzer R, Regitz-Zagrosek V, Noppinger PR. Sexually dimorphic gene expression in the heart of mice and men. J Mol Med (Berl) 2008;86:61–74.
26. Diedrich M, Tadic J, Mao L, Wacker MA, Nebrich G, Hetzer R, Regitz-Zagrosek V, Klose J. Heart protein expression related to age and sex in mice and humans. Int J Mol Med 2007;20:865–874.
27. Dworatzek E, Baczko I, Kararigas G. Effects of aging on cardiac extracellular matrix in men and women. Proteomics Clin Appl 2016;10:84–91.
28. Fliegner D, Schubert C, Penkalla A, Witt H, Kararigas G, Dworatzek E, Staub E, Martus P, Ruiz Noppinger P, Kintscher U, Gustafsson JA, Regitz-Zagrosek V. Female sex and estrogen receptor-beta attenuate cardiac remodeling and apoptosis in pressure overload. Am J Physiol Regul Integr Comp Physiol 2010;298:R1597–R1606.
29. Queiros AM, Eschen C, Fliegner D, Kararigas G, Dworatzek E, Westphal C, Sanchez Ruderisch H, Regitz-Zagrosek V. Sex- and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart. Int J Cardiol 2013; 169:331–338.
30. Mahmoodzadeh S, Dworatzek E, Fritschka S, Pham TH, Regitz-Zagrosek V. 17beta-Estradiol inhibits matrix metalloproteinase-2 transcription via MAP kinase in fibroblasts. Cardiovasc Res 2010;85:719–728.
31. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007;87:905–931.
32. Simoncini T, Mannella P, Genazzani AR. Rapid estrogen actions in the cardiovascular system. Ann N Y Acad Sci 2006;1089:424–430.
33. O’Lone R, Knorr K, Jaffe IZ, Schaffer ME, Martini PG, Karas RH, Bienkowska J, Mendelsohn ME, Hansen U. Estrogen receptors alpha and beta mediate distinct pathways of vascular gene expression, including genes involved in mitochondrial electron transport and generation of reactive oxygen species. Mol Endocrinol 2007; 21:1281–1296.
34. Prossnitz ER, Arterburn JB, Sklar LA. GPR30: a G protein-coupled receptor for estrogen. Mol Cell Endocrinol 2007;265–266:138–142.
35. Malorni W, Campesi I, Straface E, Vella S, Franconi F. Redox features of the cell: a gender perspective. Antioxid Redox Signal 2007;9:1779–1801.
36. Ortona E, Gambardella L, Barbati C, Malorni W. Membrane-associated functional estrogen receptors alpha are upregulated in cardiomyocytes under oxidative imbalance. IJC Metabolic & Endocrine 2014;5:67–69.
37. Matarrese P, Colasanti T, Ascione B, Margutti P, Franconi F, Alessandri C, Conti F, Riccieri V, Rosano G, Ortona E, Malorni W. Gender disparity in susceptibility to oxidative stress and apoptosis induced by autoantibodies specific to RLIP76 in vascular cells. Antioxid Redox Signal 2011;15:2825–2836.
38. Clocchiatti A, Cora E, Zhang Y, Dotto GP. Sexual dimorphism in cancer. Nat Rev Cancer 2016;16:330–339.
39. Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell 2012; 148:1145–1159.
40. Lagranha CJ, Deschamps A, Aponte A, Steenbergen C, Murphy E. Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females. Circ Res 2010;106:1681–1691.
41. Moulin M, Piquereau J, Mateo P, Fortin D, Rucker-Martin C, Gressette M, Lefebvre F, Gresikova M, Solgadi A, Veksler V, Garnier A, Ventura-Clapier R. Sexual dimorphism of doxorubicin-mediated cardiotoxicity: potential role of energy metabolism remodeling. Circ Heart Fail 2015;8:98–108.
42. Petrov G, Dworatzek E, Schulze TM, Dandel M, Kararigas G, Mahmoodzadeh S, Knosalla C, Hetzer R, Regitz-Zagrosek V. Maladaptive remodeling is associated with impaired survival in women but not in men after aortic valve replacement. JACC Cardiovasc Imaging 2014;7:1073–1080.
43. Petrov G, Regitz-Zagrosek V, Lehmkuhl E, Krabatsch T, Dunkel A, Dandel M, Dworatzek E, Mahmoodzadeh S, Schubert C, Becher E, Hampl H, Hetzer R. Regression of myocardial hypertrophy after aortic valve replacement: faster in women? Circulation 2010;122:S23–S28.
44. Witt H, Schubert C, Jaekel J, Fliegner D, Penkalla A, Tiemann K, Stypmann J, Roepcke S, Brokat S, Mahmoodzadeh S, Brozova E, Davidson MM, Ruiz Noppinger P, Grohe C, Regitz-Zagrosek V. Sex-specific pathways in early cardiac response to pressure overload in mice. J Mol Med (Berl) 2008;86:1013–1024.
45. Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD, Slagboom PE, Heijmans BT. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 2009;18:4046–4053.
46. Patterson AJ, Chen M, Xue Q, Xiao D, Zhang L. Chronic prenatal hypoxia induces epigenetic programming of PKC{epsilon} gene repression in rat hearts. Circ Res 2010;107:365–373.
47. Movassagh M, Vujic A, Foo R. Genome-wide DNA methylation in human heart failure. Epigenomics 2011;3:103–109.
48. Ramos RB, Fabris V, Lecke SB, Maturana MA, Spritzer PM. Association between global leukocyte DNA methylation and cardiovascular risk in postmenopausal women. BMC Med Genet 2016;17:71.
49. Regitz-Zagrosek V, Oertelt-Prigione S, Seeland U, Hetzer R. Sex and gender differences in myocardial hypertrophy and heart failure. Circ J 2010;74:1265–1273.
50. Kadkhodayan A, Lin CH, Coggan AR, Kisrieva-Ware Z, Schechtman KB, Novak E, Joseph SM, Davila-Roman VG, Gropler RJ, Dence C, Peterson LR. Sex affects myocardial blood flow and fatty acid substrate metabolism in humans with nonischemic heart failure. J Nucl Cardiol 2016. [Epub ahead of print]
51. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007;335:974.
52. Mcdonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular seque-lae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J 2008;156:918–930.
53. Ruoppolo M, Scolamiero E, Caterino M, Mirisola V, Franconi F, Campesi I. Female and male human babies have distinct blood metabolomic patterns. Mol Biosyst 2015;11:2483–2492.
54. Franconi F, Rosano G, Campesi I. Need for gender-specific pre-analytical testing: the dark side of the moon in laboratory testing. Int J Cardiol 2015;179:514–535.
55. Regitz-Zagrosek V. Sex and Gender Differences in Pharmacology. In: V. Regitz-Zagrosek (ed). Handbook of Experimental Pharmacology 214. Springer Verlag; 2012.
56. Zucker I, Beery AK. Males still dominate animal studies. Nature 2010;465:690.
57. Yoon DY, Mansukhani NA, Stubbs VC, Helenowski IB, Woodruff TK, Kibbe MR. Sex bias exists in basic science and translational surgical research. Surgery 2014; 156:508–516.
58. Unsold B, Kaul A, Sbroggio M, Schubert C, Regitz-Zagrosek V, Brancaccio M, Damilano F, Hirsch E, Van Bilsen M, Munts C, Sipido K, Bito V, Detre E, Wagner NM, Schafer K, Seidler T, Vogt J, Neef S, Bleckmann A, Maier LS, Balligand JL, Bouzin C, Ventura-Clapier R, Garnier A, Eschenhagen T, El-Armouche A, Knoll R, Tarone G, Hasenfuss G. Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction. Cardiovasc Res 2014;101:97–107.
59. Sbroggio M, Bertero A, Velasco S, Fusella F, De Blasio E, Bahou WF, Silengo L, Turco E, Brancaccio M, Tarone G. ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1. J Cell Sci 2011;124:3515–3524.
60. Kassi E, Spilioti E, Nasiri-Ansari N, Adamopoulos C, Moutsatsou P, Papapanagiotou A, Siasos G, Tousoulis D, Papavassiliou AG. Vascular inflammation and atherosclerosis: the role of estrogen receptors. Curr Med Chem 2015;22:2651–2665.
61. Gupte AA, Pownall HJ, Hamilton DJ. Estrogen: an emerging regulator of insulin action and mitochondrial function. J Diabetes Res 2015;2015:916585.
62. Billon-Gales A, Fontaine C, Filipe C, Douin-Echinard V, Fouque MJ, Flouriot G, Gourdy P, Lenfant F, Laurell H, Krust A, Chambon P, Arnal JF. The transactivating function 1 of estrogen receptor alpha is dispensable for the vasculoprotective actions of 17beta-estradiol. Proc Natl Acad Sci U S A 2009;106:2053–2058.
63. Billon-Gales A, Krust A, Fontaine C, Abot A, Flouriot G, Toutain C, Berges H, Gadeau AP, Lenfant F, Gourdy P, Chambon P, Arnal JF. Activation function 2 (AF2) of estrogen receptor-alpha is required for the atheroprotective action of estradiol but not to accelerate endothelial healing. Proc Natl Acad Sci U S A 2011; 108:13311–13316.
64. Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, Drougard A, Rajan S, Laine M, Milon A, Muller I, Henrion D, Adlanmerini M, Valera MC, Gompel A, Gerard C, Pequeux C, Mestdagt M, Raymond-Letron I, Knauf C, Ferriere F, Valet P, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Lenfant F, Greene GL, Foidart JM, Arnal JF. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation. EMBO Mol Med 2014;6:1328–1346.
65. Jankowska EA, Drohomirecka A, Ponikowska B, Witkowska A, Lopuszanska M, Szklarska A, Borodulin-Nadzieja L, Banasiak W, Poole-Wilson PA, Ponikowski P. Deficiencies in circulating testosterone and dehydroepiandrosterone sulphate, and depression in men with systolic chronic heart failure. Eur J Heart Fail 2010; 12:966–973.
66. Giannetta E, Feola T, Gianfrilli D, Pofi R, Dall’Armi V, Badagliacca R, Barbagallo F, Lenzi A, Isidori AM. Is chronic inhibition of phosphodiesterase type 5 cardioprotec-tive and safe? A meta-analysis of randomized controlled trials. BMC Med 2014;12:185.
67. Sasaki H, Nagayama T, Blanton RM, Seo K, Zhang M, Zhu G, Lee DI, Bedja D, Hsu S, Tsukamoto O, Takashima S, Kitakaze M, Mendelsohn ME, Karas RH, Kass DA, Takimoto E. PDE5 inhibitor efficacy is estrogen dependent in female heart disease. J Clin Invest 2014;124:2464–2471.
68. Taylor KE, Vallejo-Giraldo C, Schaible NS, Zakeri R, Miller VM. Reporting of sex as a variable in cardiovascular studies using cultured cells. Biol Sex Differ 2011;2:11.
69. Shah K, Mccormack CE, Bradbury NA. Do you know the sex of your cells? Am J Physiol Cell Physiol 2014;306:C3–C18.
70. Pellegrini M, Bulzomi P, Lecis M, Leone S, Campesi I, Franconi F, Marino M. Endocrine disruptors differently influence estrogen receptor beta and androgen receptor in male and female rat VSMC. J Cell Physiol 2014;229:1061–1068.
71. Franconi F, Seghieri G, Canu S, Straface E, Campesi I, Malorni W. Are the available experimental models of type 2 diabetes appropriate for a gender perspective? Pharmacol Res 2008;57:6–18.
72. Reichelt ME, Mellor KM, Bell JR, Chandramouli C, Headrick JP, Delbridge LM. Sex, sex steroids, and diabetic cardiomyopathy: making the case for experimental focus. Am J Physiol Heart Circ Physiol 2013;305:H779–H792.
73. Murphy E, Steenbergen C. Gender-based differences in mechanisms of protection in myocardial ischemia-reperfusion injury. Cardiovasc Res 2007;75:478–486.
74. Prendergast BJ, Onishi KG, Zucker I. Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci Biobehav Rev 2014;40:1–5.
75. Becker JB, Prendergast BJ, Liang JW. Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. Biol Sex Differ 2016;7:34.
76. Harvey PA, Leinwand LA. Dietary phytoestrogens present in soy dramatically increase cardiotoxicity in male mice receiving a chemotherapeutic tyrosine kinase inhibitor. Mol Cell Endocrinol 2015;399:330–335.
77. Clayton JA. Studying both sexes: a guiding principle for biomedicine. FASEB J 2016;30:519–524.
78. Arnold AP, Chen X. What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol 2009;30:1–9.
79. Grgurevic N, Budefeld T, Spanic T, Tobet SA, Majdic G. Evidence that sex chromosome genes affect sexual differentiation of female sexual behavior. Horm Behav 2012;61:719–724.
80. Guo Y, Flaherty MP, Wu WJ, Tan W, Zhu X, Li Q, Bolli R. Genetic background, gender, age, body temperature, and arterial blood pH have a major impact on myocardial infarct size in the mouse and need to be carefully measured and/or taken into account: results of a comprehensive analysis of determinants of infarct size in 1,074 mice. Basic Res Cardiol 2012;107:288.
81. Tannenbaum C, Schwarz JM, Clayton JA, De Vries GJ, Sullivan C. Evaluating sex as a biological variable in preclinical research: the devil in the details. Biol Sex Differ 2016;7:13.
82. Johnson J, Sharman Z, Vissandjee B, Stewart DE. Does a change in health research funding policy related to the integration of sex and gender have an impact? PLoS One 2014;9:e99900.
83. Ritz SA, Antle DM, Cote J, Deroy K, Fraleigh N, Messing K, Parent L, St-Pierre J, Vaillancourt C, Mergler D. First steps for integrating sex and gender considerations into basic experimental biomedical research. FASEB J 2014;28:4–13.
84. Klein SL, Schiebinger L, Stefanick ML, Cahill L, Danska J, De Vries GJ, Kibbe MR, Mccarthy MM, Mogil JS, Woodruff TK, Zucker I. Opinion: sex inclusion in basic research drives discovery. Proc Natl Acad Sci U S A 2015;112:5257–5258.
85. Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, Martin LJ, Austin JS, Sotocinal SG, Chen D, Yang M, Shi XQ, Huang H, Pillon NJ, Bilan PJ, Tu Y, Klip A, Ji RR, Zhang J, Salter MW, Mogil JS. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci 2015;18:1081–1083.
86. Miller VM, Reckelhoff JF. Sex as a biological variable: now what?! Physiology (Bethesda) 2016;31:78–80.
87. Maric-Bilkan C, Arnold AP, Taylor DA, Dwinell M, Howlett SE, Wenger N, Reckelhoff JF, Sandberg K, Churchill G, Levin E, Lundberg MS. Report of the National Heart, Lung, and Blood Institute Working Group on Sex Differences Research in Cardiovascular Disease: scientific questions and challenges. Hypertension 2016;67:802–807.