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The X Factor: Accounting for Sex in Biomedical Research Einstein, Gillian; Kovalchuk, Olga; Mogil, Jeffrey 2010

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nov • 23 • 2010 innovations in gender, sex & health research 1/26 gillian einstein · laboratory of cognitive neuroscience and women’s health departments of pyschology and public health sciences · university of torontonov • 23 • 2010 innovations in gender, sex & health research 2/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 3/26 If politics is the art of the possible, research is surely the art of the soluble. (medawar, 1969, p. 97)nov • 23 • 2010 innovations in gender, sex & health research 4/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 5/26 1016 Date 5/21/07  5/28/07  6/4/07  6/11/07  6/18/07  6/25/07  7/2/07  7/9/07  E 1G  ng/m L 0 20 40 60 80 100 120 140 160 180 200 P dG  ug/m L 0 2 4 6 8 10 12 14 16 18 20 1016 Date vs 1016 E1G ng/mL 1016 Date vs 1016 PdG ug/mL Max E1G: 6/2/07, 28.4&7/1, 32.1 Max PdG: 6/10/07, 6.1 ?Ovulatory low E1G 1013 Date 3/26/07  4/2/07  4/9/07  4/16/07  4/23/07  4/30/07  5/7/07  E 1G  ng/m L 0 20 40 60 80 1 0 120 140 160 180 200 P dG  ug/m L 0 2 4 6 8 10 12 14 16 18 20 1013 Date vs 1013 E1G ng/mL 1013 Date vs 1013 PdG ug/mL Max E1G: 4/10/07, 126 Max PdG: 4/16/07, 17.9 Ovulatory The Human Menstrual Cycle Day of Cycle 0 5 10 15 20 25 30 E1G  ng/m L 0 20 40 60 80 100 120 140 160 180 200 PdG  ug/m L 0 2 4 6 8 10 12 14 16 18 20 E1G ng/mL PdG ng/mL E1G baseline         35 PdG baseline           2 Luteal Phase PdG>BL Early Follicular PdG&E1G<BL Late Follicular E1G>BL PdG<BLnov • 23 • 2010 innovations in gender, sex & health research 6/26 daily mood variesnov • 23 • 2010 innovations in gender, sex & health research 7/26 mood & menstrual cycle phase 0 10 20 30 40 50 60 Positive Negative D L Q  R at in g  ( /100 ) Mood Early Follicular Late Follicular Early Luteal Late Lutealnov • 23 • 2010 innovations in gender, sex & health research 8/26 mood & estrogens mood & progestagens 0 20 40 60 80 100 0 50 100 150 D L Q  Ra tin g  ( /1 0 0 ) E1G  Concentration (ng/mL) 0 20 40 60 80 100 0 10 20 30 40 D L Q  Ra tin g  ( /1 0 0 ) E1G Concentration (ng/mL) 0 20 40 60 80 100 0 20 40 60 80 100 D L Q  Ra tin g E1G Concentration (ng/mL) 0 20 40 60 80 100 0 5 10 15 20 D L Q  Ra tin g  ( /1 0 0 ) PdG Concentration (ug/mL) 0 20 40 60 80 100 0 2 4 6 8 D L Q  Ra tin g  ( /1 0 0 ) PdG Concentration (ug/mL) 0 20 40 60 80 100 0 0.5 1 1.5 2 2.5 D L Q  Ra tin g  ( /1 0 0 ) PdG Concentration (ug/mL)nov • 23 • 2010 innovations in gender, sex & health research 9/26 variations within a sex • there is a relationship between daily mood and daily hormone levels but • mood does not correlate with one stage of the menstrual cycle (such as premenstrual or late luteal phase) • population and individual results differ • need to measure daily hormones for each individualnov • 23 • 2010 innovations in gender, sex & health research 10/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 11/26 • women with brca1/2 mutations have a 45 - 87% lifetime risk of developing breast cancer and 15-45% risk of developing ovarian cancer. • prophylactic bilateral salpingo-oophorectomy (pso), the surgical removal of both ovaries and fallopian tubes reduces risk of breast cancer by 50% and ovarian cancer by 80%. but what happens to the brain? • bso results in the rapid reduction of 17beta-estradiol, triggering surgical menopause, as many as 10 years prior to natural menopause. • estrogen receptors are found throughout the brain especially in the frontal cortex and hippocampus . estrogens are implicated in verbal, spatial and working memory. brca1/2 mutationsnov • 23 • 2010 innovations in gender, sex & health research 12/26 • age control (n=8) 40-50 years old pre or peri-menopausal no hormone • bso (n=8) brca1/2 mutation 39-51 years old 6 months to 8 years post-oophorectomy no serms or ais 3 women on ert BSO Age Control BRCA Control age 44.5 (5.043) 44.53 (2.560) 34.00 (1.155) body mass index 23.06 (2.783) 23.95 (4.435) 22.55 (1.630) education (in years) 16.75 (1.669) 18.13 (1.533) 16.75 (2.630) iq (estimated by naart) 110.25 (7.340) 110.97 (6.477) 110.445 (7.437) e1g (ng/ml) 0.00 – 40.76 4.94 – 37.30 7.46 – 46.88 pdg (μg/ ml) 0.05 – 0.57 0.11 – 8.43 0.23 – 2.93 • brca control (n=4) brca1/2 mutation 34-35 years old no bso 1 woman on oral contraceptivesnov • 23 • 2010 innovations in gender, sex & health research 13/26 logical memory ravlt 0 5 10 15 Immediate Delayed O bj e ct  Di s plac e m e n t ( c m ) Trial BSO Age Control BRCA Control object placement 5 7 9 11 13 15 0 1 2 3 4 5 6 7 8Word s  recal le d Time since oophorectomy … A1nov • 23 • 2010 innovations in gender, sex & health research 14/26 systems interconnections surgery on the reproductive system affects the nervous system • verbal memory performance decreases post oophorectomy • time since oophorectomy is correlated with decreased performance on short delay recall but • regression and correlation analyses suggest that improved spatial memory correlates with decreased estrogensnov • 23 • 2010 innovations in gender, sex & health research 15/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 16/26 95% girls in somalia undergo female genital circumcision/mutilation/cutting (fgc) between the ages of 5 & 13 nov • 23 • 2010 innovations in gender, sex & health research 17/26 are there neurobiological repercussions? bulbocavernosis sling around shaft of clitoris, surrounds vaginal opening ischiocavernosus surrounds clitoral crux, contracts during orgasm superficial transverse perineal underlies labia minora deep transverse perineal underlies labia majora pudendal clitoris, perineum & inner thigh hypogastric cervix & proximal 3/5 uterus pelvic vagina, cervix, perineal skin vagus cervix & deep pelvis http://www.uth.tmc.edu/scriptorium/gallery/kelly/i1 1-1.htmlnov • 23 • 2010 innovations in gender, sex & health research 18/26 1)what is it like to be you? 2)how do standardized measurements relate to what you are saying? 3)how do physiological tests relate to what you are saying? 4)does your perception/response change with environment/how you are treated? 1st 3rd 2nd 1) interviews—themes of pain 2) mcgill—pain 3) general health questionnaire & medical history 4) qst • quantitative • physiological • qualitative very mixed methods (vmm) 6* 12 9 3nov • 23 • 2010 innovations in gender, sex & health research 19/26 aches and pains of life, work very hard, enjoy sex with husband, circumcision is just something everyone does; it’s normal many begged their parents to let them be circumcised fathers/uncles not in favour—mother sees to having it done sexual desire is not absent  pa r ti c ip a nt  1 pa r ti c ip a nt  3  in t e r v ie w  typ e  interpreter  no interpreter  bi r t h  p lac e  mogadishu mogadishu cu rr en t  ag e  40 34 ye a r le av ing  s o m a lia  left somalia for italy in 1982, came to  canada in 1991 1990/1991 edu ca t io n  lev e l school in somalia, esl in canada post-secondary, college f gc  a g e  10 10 f gc  w h e r e  clinic hospital f gc  a ne st he s ia  yes yes f gc  p r ac t it io n e r  doctor  (male) doctor  pa r ent a l in v o lv eme nt  mother and  father want mother  wanted and father did not  support  f gc  e x p e r ien ce  other people  went thru a lot  of procedures   people fro m city/smal town totally different . she's from city. she got lighter circ than other s. fgc wasn't as bad as expected, doctor s, nurses normal hospital - other s stories  from friends  of midwives. "two different procedures" h ers versus friend.  # ch ild r en  3 1 t ype  o f  b ir t h  daughter=c -section in italy; sons born in canada vaginal b io me d  ex p e r ie n ce  in  c a n a d a  shocked when move to canada, circ as bad.  docs/nurses in canada treat  women with fgc differently.  q u a lit a t ive  r ep o r t s o f  pai n  sensitive, painful neck, more sens than pain, can be pleasure; back when lifting. hard to get up in a.m., whole- body ache ; sometime s rests after work, lies down.  pain in sex inside vagina, sharp. ears, breasts , neck, sensitive. too busy working to have pain, not  feeling anything. tired in evening, busy. neck, back, stress, ache.  but stretching legs wide hurts , difficult, perinium pain. body feels fine, feels good in her body. still has feeling, whereas others  affected by circ have no feeling.  t r a it s  o f  in t e r v iew  "accept", no choice, "proud" "culture" belonging, cultural- feeling not much talk about se x in somalia re: how to handle with fgc. girls still in shell, of being a girl.  everyone talks about fgc as fact, something to  be proud  of. fgc=trdition,  people would tease.   mc g ill sf 2009: knees - throb  6; shooting 6; hot  burning 7; tiring 6, fearful 5, sickening 5, pain caused by light touch 5; back (in winter) sharp 5, hot  burning 5, tiring 5; wrists/hands: sharp 5, hot/burn("fever " in  jan & dec) 5/6, aching 6, heavy 5, tend er 5, fearful 6, punishing cruel 6 headache o: 2.32, c: 3.83, i: 0.83, a: 4.25, n: 1.00 back o: 2.55, c: 4.50, i: 2.83, a: 1.75, n: 0.83  g h q  6/10 8-9/10 vu lv a r  a p p e a r a n c e  clitoris totally removed ; labia minora - totally removed; labia majora - intact;  stitched? clitoris totally removed ; l minora totally removed ; l majora intact but stitch ed  qs t  12:00=40g, needles 1; 3:00=45g, burning 2; 6:00=80g, like a scratch 2; 9:00=250g, like a needle 2 12:00 = t until 300g; 3:00 = 300g; 6:00 = 150g; 9:00 = 25g, pressure   nov • 23 • 2010 innovations in gender, sex & health research 20/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 21/26 writes on the bodynov • 23 • 2010 innovations in gender, sex & health research 22/26 still to learn: how is the female body surface laid out in the brain? we don’t know. where are the uterus, ovaries, internal clitoris located? we don’t know how does the representation change with the menstrual cycle? pregnancy? menopause? bso? fgc? mastectomy? labioplasty?nov • 23 • 2010 innovations in gender, sex & health research 23/26 plan introduction i · variantions within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epiloguenov • 23 • 2010 innovations in gender, sex & health research 24/26 • biological diversity exists within a category • the body has no independent parts • context is critical • the world writes on the body in the context of the CNS, the world makes bodies of difference not bodies of absence human biology of diversity when considering the human body various points of view, genetics, sex, age, time of day, time of month, language, culture, geography sex • gendernov • 23 • 2010 innovations in gender, sex & health research 25/26 emily glazer, ba deanna duplessis, mph naila karim, msc kimberly blom, ba janice du mont, edd robin mason, phd jan angus, phd allen gordon, md kowser omer-hashi sheila dunn, md caroline pukall, phd research teams estrogens & mood estrogens & cognition neurobiological effects of fgc mapping an hermunculous deborah schwartz, msc sarah romans, md mary jane desouza, phd soumia meiyappan, msc astrid bellem, bs deborah schwartz, msc amy finch, ma steven narod, md mary tierney, phd elizabeth hampson, phs paula di noto, msc leorra newman, bs dora landowski shelley wall, phd lubheen baghat halima arush michael marxen, phd fred tam, phd simon graham, bs and… mood & daily life sarah romans, md donna stewart, md kathryn morgan, phd brenda toner, phd anthony levitt, md david kreindler, md sheila laredo, mdnov • 23 • 2010 innovations in gender, sex & health research 26/26 maryann barre habiba adan hawa abdi fgc community advisory group nov • 23 • 2010 innovations in gender, sex & health research 1/26 gillian einstein · laboratory of cognitive neuroscience and women’s health departments of pyschology and public health sciences · university of torontonov • 23 • 2010 innovations in gender, sex & health research 2/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 3/26 If politics is the art of the possible, research is surely the art of the soluble. (medawar, 1969, p. 97)nov • 23 • 2010 innovations in gender, sex & health research 4/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 5/26 1016 Date 5/21/07  5/28/07  6/4/07  6/11/07  6/18/07  6/25/07  7/2/07  7/9/07  E 1G  ng/m L 0 20 40 60 80 100 120 140 160 180 200 P dG  ug/m L 0 2 4 6 8 10 12 14 16 18 20 1016 Date vs 1016 E1G ng/mL 1016 Date vs 1016 PdG ug/mL Max E1G: 6/2/07, 28.4&7/1, 32.1 Max PdG: 6/10/07, 6.1 ?Ovulatory low E1G 1013 Date 3/26/07  4/2/07  4/9/07  4/16/07  4/23/07  4/30/07  5/7/07  E 1G  ng/m L 0 20 40 60 80 1 0 120 140 160 180 200 P dG  ug/m L 0 2 4 6 8 10 12 14 16 18 20 1013 Date vs 1013 E1G ng/mL 1013 Date vs 1013 PdG ug/mL Max E1G: 4/10/07, 126 Max PdG: 4/16/07, 17.9 Ovulatory The Human Menstrual Cycle Day of Cycle 0 5 10 15 20 25 30 E1G  ng/m L 0 20 40 60 80 100 120 140 160 180 200 PdG  ug/m L 0 2 4 6 8 10 12 14 16 18 20 E1G ng/mL PdG ng/mL E1G baseline         35 PdG baseline           2 Luteal Phase PdG>BL Early Follicular PdG&E1G<BL Late Follicular E1G>BL PdG<BLnov • 23 • 2010 innovations in gender, sex & health research 6/26 daily mood variesnov • 23 • 2010 innovations in gender, sex & health research 7/26 mood & menstrual cycle phase 0 10 20 30 40 50 60 Positive Negative D L Q  R at in g  ( /100 ) Mood Early Follicular Late Follicular Early Luteal Late Lutealnov • 23 • 2010 innovations in gender, sex & health research 8/26 mood & estrogens mood & progestagens 0 20 40 60 80 100 0 50 100 150 D L Q  Ra tin g  ( /1 0 0 ) E1G  Concentration (ng/mL) 0 20 40 60 80 100 0 10 20 30 40 D L Q  Ra tin g  ( /1 0 0 ) E1G Concentration (ng/mL) 0 20 40 60 80 100 0 20 40 60 80 100 D L Q  Ra tin g E1G Concentration (ng/mL) 0 20 40 60 80 100 0 5 10 15 20 D L Q  Ra tin g  ( /1 0 0 ) PdG Concentration (ug/mL) 0 20 40 60 80 100 0 2 4 6 8 D L Q  Ra tin g  ( /1 0 0 ) PdG Concentration (ug/mL) 0 20 40 60 80 100 0 0.5 1 1.5 2 2.5 D L Q  Ra tin g  ( /1 0 0 ) PdG Concentration (ug/mL)nov • 23 • 2010 innovations in gender, sex & health research 9/26 variations within a sex • there is a relationship between daily mood and daily hormone levels but • mood does not correlate with one stage of the menstrual cycle (such as premenstrual or late luteal phase) • population and individual results differ • need to measure daily hormones for each individualnov • 23 • 2010 innovations in gender, sex & health research 10/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 11/26 • women with brca1/2 mutations have a 45 - 87% lifetime risk of developing breast cancer and 15-45% risk of developing ovarian cancer. • prophylactic bilateral salpingo-oophorectomy (pso), the surgical removal of both ovaries and fallopian tubes reduces risk of breast cancer by 50% and ovarian cancer by 80%. but what happens to the brain? • bso results in the rapid reduction of 17beta-estradiol, triggering surgical menopause, as many as 10 years prior to natural menopause. • estrogen receptors are found throughout the brain especially in the frontal cortex and hippocampus . estrogens are implicated in verbal, spatial and working memory. brca1/2 mutationsnov • 23 • 2010 innovations in gender, sex & health research 12/26 • age control (n=8) 40-50 years old pre or peri-menopausal no hormone • bso (n=8) brca1/2 mutation 39-51 years old 6 months to 8 years post-oophorectomy no serms or ais 3 women on ert BSO Age Control BRCA Control age 44.5 (5.043) 44.53 (2.560) 34.00 (1.155) body mass index 23.06 (2.783) 23.95 (4.435) 22.55 (1.630) education (in years) 16.75 (1.669) 18.13 (1.533) 16.75 (2.630) iq (estimated by naart) 110.25 (7.340) 110.97 (6.477) 110.445 (7.437) e1g (ng/ml) 0.00 – 40.76 4.94 – 37.30 7.46 – 46.88 pdg (μg/ ml) 0.05 – 0.57 0.11 – 8.43 0.23 – 2.93 • brca control (n=4) brca1/2 mutation 34-35 years old no bso 1 woman on oral contraceptivesnov • 23 • 2010 innovations in gender, sex & health research 13/26 logical memory ravlt 0 5 10 15 Immediate Delayed O bj e ct  Di s plac e m e n t ( c m ) Trial BSO Age Control BRCA Control object placement 5 7 9 11 13 15 0 1 2 3 4 5 6 7 8Word s  recal le d Time since oophorectomy … A1nov • 23 • 2010 innovations in gender, sex & health research 14/26 systems interconnections surgery on the reproductive system affects the nervous system • verbal memory performance decreases post oophorectomy • time since oophorectomy is correlated with decreased performance on short delay recall but • regression and correlation analyses suggest that improved spatial memory correlates with decreased estrogensnov • 23 • 2010 innovations in gender, sex & health research 15/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 16/26 95% girls in somalia undergo female genital circumcision/mutilation/cutting (fgc) between the ages of 5 & 13 nov • 23 • 2010 innovations in gender, sex & health research 17/26 are there neurobiological repercussions? bulbocavernosis sling around shaft of clitoris, surrounds vaginal opening ischiocavernosus surrounds clitoral crux, contracts during orgasm superficial transverse perineal underlies labia minora deep transverse perineal underlies labia majora pudendal clitoris, perineum & inner thigh hypogastric cervix & proximal 3/5 uterus pelvic vagina, cervix, perineal skin vagus cervix & deep pelvis http://www.uth.tmc.edu/scriptorium/gallery/kelly/i1 1-1.htmlnov • 23 • 2010 innovations in gender, sex & health research 18/26 1)what is it like to be you? 2)how do standardized measurements relate to what you are saying? 3)how do physiological tests relate to what you are saying? 4)does your perception/response change with environment/how you are treated? 1st 3rd 2nd 1) interviews—themes of pain 2) mcgill—pain 3) general health questionnaire & medical history 4) qst • quantitative • physiological • qualitative very mixed methods (vmm) 6* 12 9 3nov • 23 • 2010 innovations in gender, sex & health research 19/26 aches and pains of life, work very hard, enjoy sex with husband, circumcision is just something everyone does; it’s normal many begged their parents to let them be circumcised fathers/uncles not in favour—mother sees to having it done sexual desire is not absent  pa r ti c ip a nt  1 pa r ti c ip a nt  3  in t e r v ie w  typ e  interpreter  no interpreter  bi r t h  p lac e  mogadishu mogadishu cu rr en t  ag e  40 34 ye a r le av ing  s o m a lia  left somalia for italy in 1982, came to  canada in 1991 1990/1991 edu ca t io n  lev e l school in somalia, esl in canada post-secondary, college f gc  a g e  10 10 f gc  w h e r e  clinic hospital f gc  a ne st he s ia  yes yes f gc  p r ac t it io n e r  doctor  (male) doctor  pa r ent a l in v o lv eme nt  mother and  father want mother  wanted and father did not  support  f gc  e x p e r ien ce  other people  went thru a lot  of procedures   people fro m city/smal town totally different . she's from city. she got lighter circ than other s. fgc wasn't as bad as expected, doctor s, nurses normal hospital - other s stories  from friends  of midwives. "two different procedures" h ers versus friend.  # ch ild r en  3 1 t ype  o f  b ir t h  daughter=c -section in italy; sons born in canada vaginal b io me d  ex p e r ie n ce  in  c a n a d a  shocked when move to canada, circ as bad.  docs/nurses in canada treat  women with fgc differently.  q u a lit a t ive  r ep o r t s o f  pai n  sensitive, painful neck, more sens than pain, can be pleasure; back when lifting. hard to get up in a.m., whole- body ache ; sometime s rests after work, lies down.  pain in sex inside vagina, sharp. ears, breasts , neck, sensitive. too busy working to have pain, not  feeling anything. tired in evening, busy. neck, back, stress, ache.  but stretching legs wide hurts , difficult, perinium pain. body feels fine, feels good in her body. still has feeling, whereas others  affected by circ have no feeling.  t r a it s  o f  in t e r v iew  "accept", no choice, "proud" "culture" belonging, cultural- feeling not much talk about se x in somalia re: how to handle with fgc. girls still in shell, of being a girl.  everyone talks about fgc as fact, something to  be proud  of. fgc=trdition,  people would tease.   mc g ill sf 2009: knees - throb  6; shooting 6; hot  burning 7; tiring 6, fearful 5, sickening 5, pain caused by light touch 5; back (in winter) sharp 5, hot  burning 5, tiring 5; wrists/hands: sharp 5, hot/burn("fever " in  jan & dec) 5/6, aching 6, heavy 5, tend er 5, fearful 6, punishing cruel 6 headache o: 2.32, c: 3.83, i: 0.83, a: 4.25, n: 1.00 back o: 2.55, c: 4.50, i: 2.83, a: 1.75, n: 0.83  g h q  6/10 8-9/10 vu lv a r  a p p e a r a n c e  clitoris totally removed ; labia minora - totally removed; labia majora - intact;  stitched? clitoris totally removed ; l minora totally removed ; l majora intact but stitch ed  qs t  12:00=40g, needles 1; 3:00=45g, burning 2; 6:00=80g, like a scratch 2; 9:00=250g, like a needle 2 12:00 = t until 300g; 3:00 = 300g; 6:00 = 150g; 9:00 = 25g, pressure   nov • 23 • 2010 innovations in gender, sex & health research 20/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 21/26 writes on the bodynov • 23 • 2010 innovations in gender, sex & health research 22/26 still to learn: how is the female body surface laid out in the brain? we don’t know. where are the uterus, ovaries, internal clitoris located? we don’t know how does the representation change with the menstrual cycle? pregnancy? menopause? bso? fgc? mastectomy? labioplasty?nov • 23 • 2010 innovations in gender, sex & health research 23/26 plan introduction i · variantions within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epiloguenov • 23 • 2010 innovations in gender, sex & health research 24/26 • biological diversity exists within a category • the body has no independent parts • context is critical • the world writes on the body in the context of the CNS, the world makes bodies of difference not bodies of absence human biology of diversity when considering the human body various points of view, genetics, sex, age, time of day, time of month, language, culture, geography sex • gendernov • 23 • 2010 innovations in gender, sex & health research 25/26 emily glazer, ba deanna duplessis, mph naila karim, msc kimberly blom, ba janice du mont, edd robin mason, phd jan angus, phd allen gordon, md kowser omer-hashi sheila dunn, md caroline pukall, phd research teams estrogens & mood estrogens & cognition neurobiological effects of fgc mapping an hermunculous deborah schwartz, msc sarah romans, md mary jane desouza, phd soumia meiyappan, msc astrid bellem, bs deborah schwartz, msc amy finch, ma steven narod, md mary tierney, phd elizabeth hampson, phs paula di noto, msc leorra newman, bs dora landowski shelley wall, phd lubheen baghat halima arush michael marxen, phd fred tam, phd simon graham, bs and… mood & daily life sarah romans, md donna stewart, md kathryn morgan, phd brenda toner, phd anthony levitt, md david kreindler, md sheila laredo, mdnov • 23 • 2010 innovations in gender, sex & health research 26/26 maryann barre habiba adan hawa abdi fgc community advisory group SEX DIFFERENCES IN RADIATION RESPONSES Olga Kovalchuk, M.D./Ph.D. Professor and Board of Governors’ Research Chair CIHR Chair in Gender and Health University of Lethbridge, ABhttp://maps.grida.no/go/graphic/radiation-from-chernobylInternational Journal of Epidemiology, 2000Sources of radiation exposure: •Occupational exposure •Diagnostic and therapeutic exposure One third of people are likely to get cancer More than half will receive radiotherapy Risk of secondary radiation treatment-related malignancies Mechanisms of radiation carcinogenesis are largely unknownRADIATION EFFECTS Direct or targeted •Effects in the directly exposed cells Indirect or non-targeted effects •Effects in the neighboring unexposed cells •Persisting effects in the progeny of exposed cellsDIRECT/TARGETED EFFECTS OF IONIZING RADIATION Cell death Repair of damage Induction of clonal genetic change (mutation)INDIRECT/NON-TARGETED EFFECTS OF EXPOSURE TO IONIZING RADIATION Effects in unexposed cells and their progeny - in cells not directly hit. Genomic instability Bystander EffectsMCR 2004GENOME INSTABILITY – MOLECULAR MECHANISMS GENETIC EPIGENETICEPIGENETICS DEFINITION • Genetics: the study of heritable changes in gene function that occur with a change in the DNA sequence • Epigenetics: the study of heritable changes in gene function that occur without a change in DNA sequence. WHAT IS EPIGENETICS? The study of epigenetics strives to understand heritable changes in gene function that occur without a change in DNA sequence. This form of signaling is thought to influence the timing, the amount, and the type of products (proteins) produced by their respective genes. EPIGENETICS Rodenhiser D et al., CMAJ, 2006Jaenisch R, Bird A., Nat Genet, 2003Epigenetics of radiation-induced effects in vivoHOW DO WE STUDY RADIATION EFFECTS IN VIVO EX - completely exposed animal CT – control animal Head Exposure lead shielding EX - completely exposed animal IR – irradiated side BS – bystander side le a d  s hi e ldin g CT – control animalDNA DAMAGE UPON X-RAY EXPOSURE IN THE SPLEEN TISSUE OF WHOLE BODY AND CRANIALLY EXPOSED MALE AND FEMALE MICE (Koturbash et al, Mutat Res. 2008) 0 50 100 150 200 CT IR BS 96 H 6 H 0 50 100 150 200 CT IR BS 96 H 6 H * * Level of DNA damage, % change from control male female * CT – control animals; IR – body-exposed animals; BS – bystander/head-exposed animalsWHOLE BODY AND CRANIAL RADIATION EXPOSURE INDUCES THE SIGNIFICANT AND SEX-SPECIFIC LOSS OF DNA METHYLATION IN THE MURINE SPLEEN 0 100 200 300 400 CT IR BS 96 H 6 H 0 100 200 300 400 CT IR BS 96 H 6 H * * male female * * * * CT – control animals; IR – body-exposed animals; BS – bystander/head-exposed animals % of unmethylated CCGG sites in genome as compared to control (Koturbash et al, Mutat Res. 2008)CT B EXP CT B EXP CT H EXP CT H EXP intact   - body exposed intact  - head exposed intact  - body exposed intact  - head exposed intact animals Koturbash et al., Cell Cycle, 2008 WHOLE BODY AND CRANIAL RADIATION EXPOSURE INDUCES THE SIGNIFICANT AND SEX-SPECIFIC CHANGES IN MICRORNAOME IN THE MURINE SPLEEN WHOLE BODY AND CRANIAL RADIATION EXPOSURE INDUCES THE SIGNIFICANT AND SEX-SPECIFIC LOSS OF DNA METHYLATION IN THE MURINE SPLEEN 0 100 200 300 400 CT IR BS 96 H 6 H * * male * * 0 100 200 300 400 CT IR BS 96 H 6 H CAST 0 100 200 300 400 CT IR BS 96 H 6 H * OVX 0 100 200 300 400 CT IR BS 96 H 6 H female * * * % of unmethylated CCGG sites in genome% of unmethylated CCGG sites in genome CT – control animals; IR – body-exposed animals; BS – bystander/head-exposed animals (Koturbash et al, Mutat Res. 2008)STERILIZATION OF ANIMALS HAS ALSO LED TO: • changed miRNAome profile • diminishing of the sex-determined difference in the cellular response to radiation (apoptosis and proliferation) • altered gene expression. Koturbash et al., Cell Cycle, 2008 Koturbash et al., Mutation Res., 2008WHY DO WE STUDY SEX DIFFERENCES IN RADIATION RESPONSES? Sex differences in the frequency of radiation- induced hematological malignancies. Sex-specific radiation protection guidelines. Sex-specific treatment regiments.PATERNAL RADIATION EXPOSURE EFECTS: GERMLINE AND TRANSGENERATIONAL CONNECTIONApproximately 5% of newly diagnosed cancers will occur in patients less than 40 years of age (Canadian Cancer Society, 2008).  Approximately  1 in ~500 young adults in North America  is a childhood cancer survivor Current advances in treatment regimens, such as radiotherapy, have significantly lowered mortality rates in men of all ages (Canadian Cancer Society, 2008) One major quality-of-life issue in cancer survivors is the ability to produce healthy offspringPARENTAL IRRADIATION CAN LEAD TO DETRIMENTAL TRANSGENERATIONAL EFFECTS IN THE OFFSPRING These include •Genetic mutations •Chromosomal aberrations •Tumors The transgenerational nature of genomic instability indicates the possible involvement of epigenetic mechanisms?? ?? ? Epigenetic mechanisms involved in the transgenertional genome instabilityANALYSIS OF THE PROGENYEXPERIMENTAL SETUP C57BL/6 mice Exposed to 2.5 Gy of X-rays 7 days before mating. Mating: ~ 4 days after exposure Groups: • Non-irradiated controls (10 pairs) • Exposed Father (10 pairs) Progeny obtained and sacrificed 6 months after birth* * 0 2 4 CT   EX CT   EX  LINE1 SINE B2 R e la ti ve  q P C R  a m p lif ica tio n PATERNAL RADIATION EXPOSURE AFFECTS DNA METHYLATON OF LINE 1 AND SINE B2 RETROTRANSPOSABLE ELEMENTS IN THE THYMUS TISSUE OF THE PROGENY Filkowski, Carcinogenesis, 2010LSH1 loading LSH1 levels 0 25 50 75 100 125 C h a n g e  f ro m  c o n tr o l,  % CT             EX  *  PATERNAL RADIATION EXPOSURE DECREASES LSH PROTEIN LEVELS THE THYMUS OF PROGENY IN VIVO LSH belongs to the SNF2 family of chromatin-remodeling ATPases. It is required for efficient DNA methylation in mammals. Filkowski, Carcinogenesis, 2010PATERNAL RADIATION EXPOSURE RESULTS IN MICRORNAOME DEREGULATION IN THE THYMIC TISSUE OF THE UNEXPOSED PROGENY progeny of control progeny of exposed 0 1 2 3 p≤0.05 D IC E R  p o s it ive  c e lls p e r fi e ld  o f v ie w DICER levels progeny of control progeny of exposed Filkowski, Carcinogenesis, 2010ANALYSIS OF PATERNAL GERMLINERADIATION EXPOSURE ALTERS MICRORNAOME OF MOUSE TESTES Tamminga, Cell Cycle, 2008control exposed Mutually exclusive expression of miR-709 and BORIS in murine testes (IF and FISH analyses) INCREASED ACCUMULATION OF MIR-709 IN EXPOSED MOUSE TESTES AS DETERMINED FLUORESCENCE IN SITU (FISH) DETECTION OF MI-709 IN CRYOSECTIONS control exposedANALYSIS OF SHORT RNA MOLECULES BY DEEP SEQUENCING CT EX miRNAs piRNAsexposed control LEVELS OF MILI IN CONTROL AND EXPOSED TESTES8 9 4 2 1 8 3 4 1 3 8 5 2 0 5 2 6 3 1 9 2 7 0 7 2 4 6 0 1 5 3 9 3 1 7 6 4 9 3 7 7 7 6 8 4 3 0 5 4 1 7 1 7 5 3 0 1 1 6 9 1 9 9 2 6 1 1 8 4 1 0 8 0 6 0 8 3 6 0 100000 200000 300000 400000 500000 600000 700000 800000 900000 1000000 all LTR LINE SINE low complexity DNA simple repeat CT EX ANALYSIS OF RASIRNA (PIRNA) MOLECULES BY DEEP SEQUENCING619 1728 2277 561 428331 462 572 297 212 0 500 1000 1500 2000 2500 25 26 27 28 29 CT EX 1872 1436 765 151 30 1327 742 337 128 25 0 500 1000 1500 2000 27 28 29 30 31 CT EX SINE B1 IAPLTR1Patental germline DNA damage Altered DNA methylation Altered miRNAome Loss of piRNAome/ rasiRNAome Progeny Aberrant gene (including small RNAs) gene expression Downstream “snowball’ effects? Aberrant setting of methylation marks ? ?? ?ACKNOWLEDGEMENTS Funding: Kovalchuk group Slava Ilnytsky Jody Filkowski Natasha Singh Matt Merrifield Dmitry Litvinov Roman Anisimov Bo Wang Julian St. Hilaire Rocio Rodriguez-Juarez Lidia Luzhna Joel Stimson Munima Alam Paul Walz Corinne Sidler Stephanie Wickersham Alumni Jan Tamminga Kristy Kutanzi Igor Koturbash Mike Lowings Jonathan Loree James Meservy Collaborators: Igor Pogribny, NCTR William Bonner, NCI/NIH Olga Sedelnikova, NCI/NIH Bevin Engelward, MIT Bryan Kolb, CCBN Robert Sutherland, CCBN Eugene Berezikov, Hubrecht Institute nov • 23 • 2010 innovations in gender, sex & health research 1/26 gillian einstein · laboratory of cognitive neuroscience and women’s health departments of pyschology and public health sciences · university of torontonov • 23 • 2010 innovations in gender, sex & health research 2/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 3/26 If politics is the art of the possible, research is surely the art of the soluble. (medawar, 1969, p. 97)nov • 23 • 2010 innovations in gender, sex & health research 4/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 5/26 1016 Date 5/21/07  5/28/07  6/4/07  6/11/07  6/18/07  6/25/07  7/2/07  7/9/07  E 1G  ng/m L 0 20 40 60 80 100 120 140 160 180 200 P dG  ug/m L 0 2 4 6 8 10 12 14 16 18 20 1016 Date vs 1016 E1G ng/mL 1016 Date vs 1016 PdG ug/mL Max E1G: 6/2/07, 28.4&7/1, 32.1 Max PdG: 6/10/07, 6.1 ?Ovulatory low E1G 1013 Date 3/26/07  4/2/07  4/9/07  4/16/07  4/23/07  4/30/07  5/7/07  E 1G  ng/m L 0 20 40 60 80 1 0 120 140 160 180 200 P dG  ug/m L 0 2 4 6 8 10 12 14 16 18 20 1013 Date vs 1013 E1G ng/mL 1013 Date vs 1013 PdG ug/mL Max E1G: 4/10/07, 126 Max PdG: 4/16/07, 17.9 Ovulatory The Human Menstrual Cycle Day of Cycle 0 5 10 15 20 25 30 E1G  ng/m L 0 20 40 60 80 100 120 140 160 180 200 PdG  ug/m L 0 2 4 6 8 10 12 14 16 18 20 E1G ng/mL PdG ng/mL E1G baseline         35 PdG baseline           2 Luteal Phase PdG>BL Early Follicular PdG&E1G<BL Late Follicular E1G>BL PdG<BLnov • 23 • 2010 innovations in gender, sex & health research 6/26 daily mood variesnov • 23 • 2010 innovations in gender, sex & health research 7/26 mood & menstrual cycle phase 0 10 20 30 40 50 60 Positive Negative D L Q  R at in g  ( /100 ) Mood Early Follicular Late Follicular Early Luteal Late Lutealnov • 23 • 2010 innovations in gender, sex & health research 8/26 mood & estrogens mood & progestagens 0 20 40 60 80 100 0 50 100 150 D L Q  Ra tin g  ( /1 0 0 ) E1G  Concentration (ng/mL) 0 20 40 60 80 100 0 10 20 30 40 D L Q  Ra tin g  ( /1 0 0 ) E1G Concentration (ng/mL) 0 20 40 60 80 100 0 20 40 60 80 100 D L Q  Ra tin g E1G Concentration (ng/mL) 0 20 40 60 80 100 0 5 10 15 20 D L Q  Ra tin g  ( /1 0 0 ) PdG Concentration (ug/mL) 0 20 40 60 80 100 0 2 4 6 8 D L Q  Ra tin g  ( /1 0 0 ) PdG Concentration (ug/mL) 0 20 40 60 80 100 0 0.5 1 1.5 2 2.5 D L Q  Ra tin g  ( /1 0 0 ) PdG Concentration (ug/mL)nov • 23 • 2010 innovations in gender, sex & health research 9/26 variations within a sex • there is a relationship between daily mood and daily hormone levels but • mood does not correlate with one stage of the menstrual cycle (such as premenstrual or late luteal phase) • population and individual results differ • need to measure daily hormones for each individualnov • 23 • 2010 innovations in gender, sex & health research 10/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 11/26 • women with brca1/2 mutations have a 45 - 87% lifetime risk of developing breast cancer and 15-45% risk of developing ovarian cancer. • prophylactic bilateral salpingo-oophorectomy (pso), the surgical removal of both ovaries and fallopian tubes reduces risk of breast cancer by 50% and ovarian cancer by 80%. but what happens to the brain? • bso results in the rapid reduction of 17beta-estradiol, triggering surgical menopause, as many as 10 years prior to natural menopause. • estrogen receptors are found throughout the brain especially in the frontal cortex and hippocampus . estrogens are implicated in verbal, spatial and working memory. brca1/2 mutationsnov • 23 • 2010 innovations in gender, sex & health research 12/26 • age control (n=8) 40-50 years old pre or peri-menopausal no hormone • bso (n=8) brca1/2 mutation 39-51 years old 6 months to 8 years post-oophorectomy no serms or ais 3 women on ert BSO Age Control BRCA Control age 44.5 (5.043) 44.53 (2.560) 34.00 (1.155) body mass index 23.06 (2.783) 23.95 (4.435) 22.55 (1.630) education (in years) 16.75 (1.669) 18.13 (1.533) 16.75 (2.630) iq (estimated by naart) 110.25 (7.340) 110.97 (6.477) 110.445 (7.437) e1g (ng/ml) 0.00 – 40.76 4.94 – 37.30 7.46 – 46.88 pdg (μg/ ml) 0.05 – 0.57 0.11 – 8.43 0.23 – 2.93 • brca control (n=4) brca1/2 mutation 34-35 years old no bso 1 woman on oral contraceptivesnov • 23 • 2010 innovations in gender, sex & health research 13/26 logical memory ravlt 0 5 10 15 Immediate Delayed O bj e ct  Di s plac e m e n t ( c m ) Trial BSO Age Control BRCA Control object placement 5 7 9 11 13 15 0 1 2 3 4 5 6 7 8Word s  recal le d Time since oophorectomy … A1nov • 23 • 2010 innovations in gender, sex & health research 14/26 systems interconnections surgery on the reproductive system affects the nervous system • verbal memory performance decreases post oophorectomy • time since oophorectomy is correlated with decreased performance on short delay recall but • regression and correlation analyses suggest that improved spatial memory correlates with decreased estrogensnov • 23 • 2010 innovations in gender, sex & health research 15/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 16/26 95% girls in somalia undergo female genital circumcision/mutilation/cutting (fgc) between the ages of 5 & 13 nov • 23 • 2010 innovations in gender, sex & health research 17/26 are there neurobiological repercussions? bulbocavernosis sling around shaft of clitoris, surrounds vaginal opening ischiocavernosus surrounds clitoral crux, contracts during orgasm superficial transverse perineal underlies labia minora deep transverse perineal underlies labia majora pudendal clitoris, perineum & inner thigh hypogastric cervix & proximal 3/5 uterus pelvic vagina, cervix, perineal skin vagus cervix & deep pelvis http://www.uth.tmc.edu/scriptorium/gallery/kelly/i1 1-1.htmlnov • 23 • 2010 innovations in gender, sex & health research 18/26 1)what is it like to be you? 2)how do standardized measurements relate to what you are saying? 3)how do physiological tests relate to what you are saying? 4)does your perception/response change with environment/how you are treated? 1st 3rd 2nd 1) interviews—themes of pain 2) mcgill—pain 3) general health questionnaire & medical history 4) qst • quantitative • physiological • qualitative very mixed methods (vmm) 6* 12 9 3nov • 23 • 2010 innovations in gender, sex & health research 19/26 aches and pains of life, work very hard, enjoy sex with husband, circumcision is just something everyone does; it’s normal many begged their parents to let them be circumcised fathers/uncles not in favour—mother sees to having it done sexual desire is not absent  pa r ti c ip a nt  1 pa r ti c ip a nt  3  in t e r v ie w  typ e  interpreter  no interpreter  bi r t h  p lac e  mogadishu mogadishu cu rr en t  ag e  40 34 ye a r le av ing  s o m a lia  left somalia for italy in 1982, came to  canada in 1991 1990/1991 edu ca t io n  lev e l school in somalia, esl in canada post-secondary, college f gc  a g e  10 10 f gc  w h e r e  clinic hospital f gc  a ne st he s ia  yes yes f gc  p r ac t it io n e r  doctor  (male) doctor  pa r ent a l in v o lv eme nt  mother and  father want mother  wanted and father did not  support  f gc  e x p e r ien ce  other people  went thru a lot  of procedures   people fro m city/smal town totally different . she's from city. she got lighter circ than other s. fgc wasn't as bad as expected, doctor s, nurses normal hospital - other s stories  from friends  of midwives. "two different procedures" h ers versus friend.  # ch ild r en  3 1 t ype  o f  b ir t h  daughter=c -section in italy; sons born in canada vaginal b io me d  ex p e r ie n ce  in  c a n a d a  shocked when move to canada, circ as bad.  docs/nurses in canada treat  women with fgc differently.  q u a lit a t ive  r ep o r t s o f  pai n  sensitive, painful neck, more sens than pain, can be pleasure; back when lifting. hard to get up in a.m., whole- body ache ; sometime s rests after work, lies down.  pain in sex inside vagina, sharp. ears, breasts , neck, sensitive. too busy working to have pain, not  feeling anything. tired in evening, busy. neck, back, stress, ache.  but stretching legs wide hurts , difficult, perinium pain. body feels fine, feels good in her body. still has feeling, whereas others  affected by circ have no feeling.  t r a it s  o f  in t e r v iew  "accept", no choice, "proud" "culture" belonging, cultural- feeling not much talk about se x in somalia re: how to handle with fgc. girls still in shell, of being a girl.  everyone talks about fgc as fact, something to  be proud  of. fgc=trdition,  people would tease.   mc g ill sf 2009: knees - throb  6; shooting 6; hot  burning 7; tiring 6, fearful 5, sickening 5, pain caused by light touch 5; back (in winter) sharp 5, hot  burning 5, tiring 5; wrists/hands: sharp 5, hot/burn("fever " in  jan & dec) 5/6, aching 6, heavy 5, tend er 5, fearful 6, punishing cruel 6 headache o: 2.32, c: 3.83, i: 0.83, a: 4.25, n: 1.00 back o: 2.55, c: 4.50, i: 2.83, a: 1.75, n: 0.83  g h q  6/10 8-9/10 vu lv a r  a p p e a r a n c e  clitoris totally removed ; labia minora - totally removed; labia majora - intact;  stitched? clitoris totally removed ; l minora totally removed ; l majora intact but stitch ed  qs t  12:00=40g, needles 1; 3:00=45g, burning 2; 6:00=80g, like a scratch 2; 9:00=250g, like a needle 2 12:00 = t until 300g; 3:00 = 300g; 6:00 = 150g; 9:00 = 25g, pressure   nov • 23 • 2010 innovations in gender, sex & health research 20/26 plan introduction i · variations within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epilogue nov • 23 • 2010 innovations in gender, sex & health research 21/26 writes on the bodynov • 23 • 2010 innovations in gender, sex & health research 22/26 still to learn: how is the female body surface laid out in the brain? we don’t know. where are the uterus, ovaries, internal clitoris located? we don’t know how does the representation change with the menstrual cycle? pregnancy? menopause? bso? fgc? mastectomy? labioplasty?nov • 23 • 2010 innovations in gender, sex & health research 23/26 plan introduction i · variantions within a sex ii · systems interconnections iii · bodies in context iv · how the world writes on the body epiloguenov • 23 • 2010 innovations in gender, sex & health research 24/26 • biological diversity exists within a category • the body has no independent parts • context is critical • the world writes on the body in the context of the CNS, the world makes bodies of difference not bodies of absence human biology of diversity when considering the human body various points of view, genetics, sex, age, time of day, time of month, language, culture, geography sex • gendernov • 23 • 2010 innovations in gender, sex & health research 25/26 emily glazer, ba deanna duplessis, mph naila karim, msc kimberly blom, ba janice du mont, edd robin mason, phd jan angus, phd allen gordon, md kowser omer-hashi sheila dunn, md caroline pukall, phd research teams estrogens & mood estrogens & cognition neurobiological effects of fgc mapping an hermunculous deborah schwartz, msc sarah romans, md mary jane desouza, phd soumia meiyappan, msc astrid bellem, bs deborah schwartz, msc amy finch, ma steven narod, md mary tierney, phd elizabeth hampson, phs paula di noto, msc leorra newman, bs dora landowski shelley wall, phd lubheen baghat halima arush michael marxen, phd fred tam, phd simon graham, bs and… mood & daily life sarah romans, md donna stewart, md kathryn morgan, phd brenda toner, phd anthony levitt, md david kreindler, md sheila laredo, mdnov • 23 • 2010 innovations in gender, sex & health research 26/26 maryann barre habiba adan hawa abdi fgc community advisory group SEX DIFFERENCES IN RADIATION RESPONSES Olga Kovalchuk, M.D./Ph.D. Professor and Board of Governors’ Research Chair CIHR Chair in Gender and Health University of Lethbridge, ABhttp://maps.grida.no/go/graphic/radiation-from-chernobylInternational Journal of Epidemiology, 2000Sources of radiation exposure: •Occupational exposure •Diagnostic and therapeutic exposure One third of people are likely to get cancer More than half will receive radiotherapy Risk of secondary radiation treatment-related malignancies Mechanisms of radiation carcinogenesis are largely unknownRADIATION EFFECTS Direct or targeted •Effects in the directly exposed cells Indirect or non-targeted effects •Effects in the neighboring unexposed cells •Persisting effects in the progeny of exposed cellsDIRECT/TARGETED EFFECTS OF IONIZING RADIATION Cell death Repair of damage Induction of clonal genetic change (mutation)INDIRECT/NON-TARGETED EFFECTS OF EXPOSURE TO IONIZING RADIATION Effects in unexposed cells and their progeny - in cells not directly hit. Genomic instability Bystander EffectsMCR 2004GENOME INSTABILITY – MOLECULAR MECHANISMS GENETIC EPIGENETICEPIGENETICS DEFINITION • Genetics: the study of heritable changes in gene function that occur with a change in the DNA sequence • Epigenetics: the study of heritable changes in gene function that occur without a change in DNA sequence. WHAT IS EPIGENETICS? The study of epigenetics strives to understand heritable changes in gene function that occur without a change in DNA sequence. This form of signaling is thought to influence the timing, the amount, and the type of products (proteins) produced by their respective genes. EPIGENETICS Rodenhiser D et al., CMAJ, 2006Jaenisch R, Bird A., Nat Genet, 2003Epigenetics of radiation-induced effects in vivoHOW DO WE STUDY RADIATION EFFECTS IN VIVO EX - completely exposed animal CT – control animal Head Exposure lead shielding EX - completely exposed animal IR – irradiated side BS – bystander side le a d  s hi e ldin g CT – control animalDNA DAMAGE UPON X-RAY EXPOSURE IN THE SPLEEN TISSUE OF WHOLE BODY AND CRANIALLY EXPOSED MALE AND FEMALE MICE (Koturbash et al, Mutat Res. 2008) 0 50 100 150 200 CT IR BS 96 H 6 H 0 50 100 150 200 CT IR BS 96 H 6 H * * Level of DNA damage, % change from control male female * CT – control animals; IR – body-exposed animals; BS – bystander/head-exposed animalsWHOLE BODY AND CRANIAL RADIATION EXPOSURE INDUCES THE SIGNIFICANT AND SEX-SPECIFIC LOSS OF DNA METHYLATION IN THE MURINE SPLEEN 0 100 200 300 400 CT IR BS 96 H 6 H 0 100 200 300 400 CT IR BS 96 H 6 H * * male female * * * * CT – control animals; IR – body-exposed animals; BS – bystander/head-exposed animals % of unmethylated CCGG sites in genome as compared to control (Koturbash et al, Mutat Res. 2008)CT B EXP CT B EXP CT H EXP CT H EXP intact   - body exposed intact  - head exposed intact  - body exposed intact  - head exposed intact animals Koturbash et al., Cell Cycle, 2008 WHOLE BODY AND CRANIAL RADIATION EXPOSURE INDUCES THE SIGNIFICANT AND SEX-SPECIFIC CHANGES IN MICRORNAOME IN THE MURINE SPLEEN WHOLE BODY AND CRANIAL RADIATION EXPOSURE INDUCES THE SIGNIFICANT AND SEX-SPECIFIC LOSS OF DNA METHYLATION IN THE MURINE SPLEEN 0 100 200 300 400 CT IR BS 96 H 6 H * * male * * 0 100 200 300 400 CT IR BS 96 H 6 H CAST 0 100 200 300 400 CT IR BS 96 H 6 H * OVX 0 100 200 300 400 CT IR BS 96 H 6 H female * * * % of unmethylated CCGG sites in genome% of unmethylated CCGG sites in genome CT – control animals; IR – body-exposed animals; BS – bystander/head-exposed animals (Koturbash et al, Mutat Res. 2008)STERILIZATION OF ANIMALS HAS ALSO LED TO: • changed miRNAome profile • diminishing of the sex-determined difference in the cellular response to radiation (apoptosis and proliferation) • altered gene expression. Koturbash et al., Cell Cycle, 2008 Koturbash et al., Mutation Res., 2008WHY DO WE STUDY SEX DIFFERENCES IN RADIATION RESPONSES? Sex differences in the frequency of radiation- induced hematological malignancies. Sex-specific radiation protection guidelines. Sex-specific treatment regiments.PATERNAL RADIATION EXPOSURE EFECTS: GERMLINE AND TRANSGENERATIONAL CONNECTIONApproximately 5% of newly diagnosed cancers will occur in patients less than 40 years of age (Canadian Cancer Society, 2008).  Approximately  1 in ~500 young adults in North America  is a childhood cancer survivor Current advances in treatment regimens, such as radiotherapy, have significantly lowered mortality rates in men of all ages (Canadian Cancer Society, 2008) One major quality-of-life issue in cancer survivors is the ability to produce healthy offspringPARENTAL IRRADIATION CAN LEAD TO DETRIMENTAL TRANSGENERATIONAL EFFECTS IN THE OFFSPRING These include •Genetic mutations •Chromosomal aberrations •Tumors The transgenerational nature of genomic instability indicates the possible involvement of epigenetic mechanisms?? ?? ? Epigenetic mechanisms involved in the transgenertional genome instabilityANALYSIS OF THE PROGENYEXPERIMENTAL SETUP C57BL/6 mice Exposed to 2.5 Gy of X-rays 7 days before mating. Mating: ~ 4 days after exposure Groups: • Non-irradiated controls (10 pairs) • Exposed Father (10 pairs) Progeny obtained and sacrificed 6 months after birth* * 0 2 4 CT   EX CT   EX  LINE1 SINE B2 R e la ti ve  q P C R  a m p lif ica tio n PATERNAL RADIATION EXPOSURE AFFECTS DNA METHYLATON OF LINE 1 AND SINE B2 RETROTRANSPOSABLE ELEMENTS IN THE THYMUS TISSUE OF THE PROGENY Filkowski, Carcinogenesis, 2010LSH1 loading LSH1 levels 0 25 50 75 100 125 C h a n g e  f ro m  c o n tr o l,  % CT             EX  *  PATERNAL RADIATION EXPOSURE DECREASES LSH PROTEIN LEVELS THE THYMUS OF PROGENY IN VIVO LSH belongs to the SNF2 family of chromatin-remodeling ATPases. It is required for efficient DNA methylation in mammals. Filkowski, Carcinogenesis, 2010PATERNAL RADIATION EXPOSURE RESULTS IN MICRORNAOME DEREGULATION IN THE THYMIC TISSUE OF THE UNEXPOSED PROGENY progeny of control progeny of exposed 0 1 2 3 p≤0.05 D IC E R  p o s it ive  c e lls p e r fi e ld  o f v ie w DICER levels progeny of control progeny of exposed Filkowski, Carcinogenesis, 2010ANALYSIS OF PATERNAL GERMLINERADIATION EXPOSURE ALTERS MICRORNAOME OF MOUSE TESTES Tamminga, Cell Cycle, 2008control exposed Mutually exclusive expression of miR-709 and BORIS in murine testes (IF and FISH analyses) INCREASED ACCUMULATION OF MIR-709 IN EXPOSED MOUSE TESTES AS DETERMINED FLUORESCENCE IN SITU (FISH) DETECTION OF MI-709 IN CRYOSECTIONS control exposedANALYSIS OF SHORT RNA MOLECULES BY DEEP SEQUENCING CT EX miRNAs piRNAsexposed control LEVELS OF MILI IN CONTROL AND EXPOSED TESTES8 9 4 2 1 8 3 4 1 3 8 5 2 0 5 2 6 3 1 9 2 7 0 7 2 4 6 0 1 5 3 9 3 1 7 6 4 9 3 7 7 7 6 8 4 3 0 5 4 1 7 1 7 5 3 0 1 1 6 9 1 9 9 2 6 1 1 8 4 1 0 8 0 6 0 8 3 6 0 100000 200000 300000 400000 500000 600000 700000 800000 900000 1000000 all LTR LINE SINE low complexity DNA simple repeat CT EX ANALYSIS OF RASIRNA (PIRNA) MOLECULES BY DEEP SEQUENCING619 1728 2277 561 428331 462 572 297 212 0 500 1000 1500 2000 2500 25 26 27 28 29 CT EX 1872 1436 765 151 30 1327 742 337 128 25 0 500 1000 1500 2000 27 28 29 30 31 CT EX SINE B1 IAPLTR1Patental germline DNA damage Altered DNA methylation Altered miRNAome Loss of piRNAome/ rasiRNAome Progeny Aberrant gene (including small RNAs) gene expression Downstream “snowball’ effects? Aberrant setting of methylation marks ? ?? ?ACKNOWLEDGEMENTS Funding: Kovalchuk group Slava Ilnytsky Jody Filkowski Natasha Singh Matt Merrifield Dmitry Litvinov Roman Anisimov Bo Wang Julian St. Hilaire Rocio Rodriguez-Juarez Lidia Luzhna Joel Stimson Munima Alam Paul Walz Corinne Sidler Stephanie Wickersham Alumni Jan Tamminga Kristy Kutanzi Igor Koturbash Mike Lowings Jonathan Loree James Meservy Collaborators: Igor Pogribny, NCTR William Bonner, NCI/NIH Olga Sedelnikova, NCI/NIH Bevin Engelward, MIT Bryan Kolb, CCBN Robert Sutherland, CCBN Eugene Berezikov, Hubrecht Institute Sex, Gender and PainSex Prevalence of Painful Disorders (Berkley, Behav. Brain Sci., 1997) :TMD: :fibromyalgia: :migraine w/a: :CRPS: :arthritis (RA): :IBS:Basic Scientists Ignore Epidemiology vs. 55-year old female human 8-week old male Sprague Dawley ratMale Rodents are Overwhelmingly the Subjects of Basic Science Studies of Pain Mogil & Chanda, Pain, 2005 “Sex differences are to be enjoyed, not to be studied!”   Dr. Przemyslaw Marek, 1992Q.  Are Female Pain Data Really More Variable? 49°C Tail-Withdrawal Test Formalin Test (Late Phase) Mogil & Chanda, Pain, 2005 (and unpublished data) A.  NO 0 10 20 30 40 50 60 70 80 90 100 % Allodynia 0 10 20 30 40 C ou nt 0.0 0.1 0.2 Proportion per Bar Male Female SEX SNI Mechanical Allodynia Female Male Mean: 75.2% 70.5% CV: 0.23% 0.30% SECV: 0.08% 0.09%Sex Differences in Pain Sensitivity? OR vs.So Who’s More Sensitive to Pain? • FEMALES:  when differences are reported, they are virtually always in the same direction • BUT, “…deduction from known biological sex differences suggests that there are powerful sex differences in the operation of pain mechanisms.”  (Berkley, 1997) • BUT,  it depends on the type of pain and the dependent measure (Riley III et al., 1998)Males and Females Have Different Brains?! A radical hypothesis: Males and females have qualitatively different (i.e., neurochemically and genetically distinct) pain processing mechanisms. NMDA MC1R NMDA = N- met hyl - D- aspart at e recept or MC1R = mel anocort i n- 1 recept orStudy Design • 24 men; 19 women • 22 redheads; 21 non-redheads • test all for pentazocine analgesia against pain • all subjects had their MC1R gene sequenced Pentazocine Analgesia Women Men 0 20 40 60 80 100 120 0 or 1 variant 2+ variants* To ta l R at in g Ch an ge (p os t-d ru g - p re -d ru g) 2+ variants0-1 variants MC1R Female-Specific Involvement of Melanocortin-1 Receptors in k-Opioid (Pentazocine) Analgesia in Humans Mogil et al., Proc. Natl. Acad. Sci., USA, 2003 More Pain Less PainThe Price of Ignoring Sex Differences: The Story of Morphidex® Morphine + Dextromethorphan (DXMP) More Pain Less Pain Morphidex® Nemmani et al., Pain, 2004Sex-Specific Effect of Tlr4 (Toll-like receptor 4) Genetic Dysfunction on Neuropathic Mechanical Allodynia C3H/HeN (Tlr4 +/+) C3H/HeJ (Tlr4  -/-) Less Pain More Pain Sorge et al., unpublishedMale-Specific and Testosterone-Dependent Involvement of Spinal TLR4 in Chronic Pain Sorge et al., unpublishedThanks to… At McGill: Dr. Shad Smith Jennifer Ritchie Susana Sotocinal Dr. Kumar Nemmani Jean-Sebastien Austin Mona Lisa Chanda Dale J. Langford Dr. Michael LaCroix-Fralish Melissa Farmer Ara Schorscher-Petcu Dr. Andrea Bailey Dr. Robert Sorge At Illinois: Dr. Sonya (Wilson) Lehto Dr. Elissa Chesler Dr. Andrew Rankin Dr. Roger B. Fillingim (University of Florida) Dr. Benjamin Kest (College of Staten Island) The Louise and Alan Edwards Foundation

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