Kivesten kehityshäiriö ja kivessyövän e1ologia. Jaakko Koskenniemi LK, väitöskirjatutkija

Transkriptio

1 Kivesten kehityshäiriö ja kivessyövän e1ologia Jaakko Koskenniemi LK, väitöskirjatutkija

2 Sidonnaisuudet Väitöskirja- apuraha: Lastentau1en tutkimussää1ö, Suomen

3 Sisältö Kivessyövän e1ologinen malli Kiveksen kehityshäiriö Ympäristön hormonihäiritsijäkemikaalit kehityshäiriön

4 Embryo Fetus Birth Childhood Puberty Young Adult Older Adult Genetic factors Arrest of differentiation Environmental factors ICM PGC Gonocyte Pre-sp-gonium Sp-gonium Expression of embr. pluripotency genes Spermatocytes Spermatids Germ cell specific genes (pre-meiotic) TDS Delayed Gonocyte pre-cis CIS = ITGCN = TIN = GCNIS (germ cell neoplasia in situ) Rajpert-De Meyts 2006 Hum Reprod

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6 Stem-cell pluripotency-related factors are highly expressed in CIS CIS CIS CIS CIS norm CIS normal normal POU5F1 (OCT-4) NANOG Looijenga et al Rajpert-De Meyts et al Jones et al Høi-Hansen et al Hart et al Fetal testis Fetal testis TFAP2C (AP2 gamma) Høi-Hansen et al Pauls et al Fetal testis

7 Kivessyövän etiologinen malli Embryo Fetus Birth Childhood Puberty Young Adult Older Adult Genetic factors Arrest of differentiation Environmental factors ICM PGC Gonocyte Pre-sp-gonium Sp-gonium Expression of embr. pluripotency genes Spermatocytes Spermatids Germ cell specific genes (pre-meiotic) TDS GCNIS Delayed Gonocyte pre-cis Adaptation? Polyploidisation? gain of 12p (17q, X?), Epigenetic changes? Proliferation CIS with invasive capacity? Re- programming EC NON- SEMINOMAS SEMINOMA TER YST CHC Rajpert-De Meyts 2006 Hum Reprod

8 Inhibin B Testis cancer incidence Testosterone AGE (years)

9 Ympäristö ja perimän rooli kivessyövän synnyssä?

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20 Hemminki et al Eur J Cancer

21 Normal young men Sperm conc. (mill/ml) Jørgensen et al (2002, 2011), Richthoff et al (2000), Punab et al (2002), Tsarev et al (2003), Paasch et al (2008) Fernandez et al (2011)

22 Young men from the Finnish general populaaon Adverse trends in semen quality and testis cancer among Finnish men Sperm concentrations Categories of sperm concen % <15 million/ml million/ml Millions/mL p = % 80% 70% 60% 50% 69% 65% p = % Total sperm counts 30% % 21% 22% Millions % 0% 10% 13% Birth cohorts p = p = Figure 2 Frequencies of young Finnish men hav tions below 15, and above 40 million cohorts. Note the trends for more men having below 40 million ml; 31, 35 and 43% for the b Jørgensen et al 2011 IJA

23 Kiveksen kehityshäiriö Juul et al Nat Rev Endocrinol, modifed from Skakkebæk et al. 2001

24 descent in those lost to follow-up, the prevalence at 3 months in Denmark would be 2 4% and in Finland 1 2%, Piilokiveksisyyden esiintyvyys 94/ Denmark Finland Prevalence (%) / / At birth or expected At 3 mo date of delivery 14/ 1407 Boisen et al Lancet At expected date of delivery would have remained cryptorchid if Siemennesteen laatu Spontaneous testicular descent w Danish cases and 54% of the Finn expected date of delivery and 3 estimated the mean incidence rate (the probability of testicular des month) to be 0 26 in Denmark during the first 3 months, ie, cryptorchidism had a mean probab spontaneous testicular descent ev At 3 months of age Prevalence of congenital cryptorchidism in the Danish and n/ liveborn children Finnish prospective cohort/ at expected date of delivery and at Hypospadiatapauksia elävänä syntynynä 3 months of age 60 Numbers of2cryptorchid Boisen et al. 005 JCEM boys/number of boys examined are shown on 50 bars with 95% CIs. Non-palpable Inguinal Suprascrotal High scrotal Denmark Finland Denmar 0 4 (4) 0 8 (8) 0 9 (9) 7 0 (73) 0 2 (2) 0 2 (2) 0 6 (6) 0 9 (9) 0 6 (9) 0 5 (8) 0 1 (2) 1 1 (16) Kivessyöpä Number of boys is shown in parentheses. For bil were classified according to the most severe con 18 months of age is calculated on the basis of b since only boys with congenital cryptorchidism a examined at 18 months of age. Table 2: Prevalence of congenital cryp clinical subtypes THE LANCET Vol 363 April For personal use. Only reproduce with permission from The Lancet. 0 Finland Denmark

25 Working group Georg Becher, Norway Åke Bergman, Sweden (Leader) Poul Bjerregaard, Denmark Riana Bornman, South Africa Ingvar Brandt, Sweden Jerrold J. Heindel, USA Taisen Iguchi, Japan Susan Jobling, England Karen A. Kidd, Canada Andreas Kortenkamp, England Derek C.G. Muir, Canada Roseline Ochieng, Kenya Niels E. Skakkebaek, Denmark Jorma Toppari, Finland Tracey J. Woodruff, USA R. Thomas Zoeller, USA

26 Androgeenireseptoriin sitoutuvaa kemikaalia (Vinggaard et al. 2008) WHO State of Science of Endocrine Disrup1ng Chemicals

27 Kivessyöpä Odds Ratio (95% CI) kivessyöpäpo1laan äi1ä + 61 samanikäisen miehen äi1ä PCB, p,p - DDE, klordaanin, ja PBDE:n määritys äidin seerumista lapsen diagnoosin jälkeen PBDE, PCB, HCB, PCB- TEq yhteyksissä kohonneeseen piilokiveksisyyden riskiin 0 HCB p.p DDE PBDESum of 37 Sum PCBs HCB p,p`- DDE PCB Chlordanes of ChlordanesTEq TEq Hardell et al IJA PBDE

28 families 2562 boys Katharina Main

29 Tanskalaispojat al1stuvat suuremmalle kemikaalipitoisuudelle 6,0 5,0 RelaAve differences 4,0 3,0 2,0 1,0 0,0 Finland Denmark Krysiak- Baltyn et al IJA

30 10 most important chemicals in each of the two principal components are listed as follows: PCI: 1,2,3,4,7,8-HCDD, PCB 209, PCB 156, PCB 189, PCB 170, PCB 157, PCB 194, PCB 180, o.p -DDE, PCB 81. PC2: 1,2,3,6,7,8- HCDD, 1,2,3,4,6,7,8-HepCDD, Mirex, Suomalaisten ja tanskalaisten 1,2,3,4,6,7,8-HepCDF, OCDD, PeBB, BDe 154,1,2,3,4,7,8-HCDD, PCB 49, Octachlorostyrene. kemikaalial1stuksessa on PC eroja 1 Chemicals in breast milk 35 Danish Finnish PC 2 Figure 3 Two-dimensional scatter plot shows the concentration of the two chemicals 1,2,3,4,7,8-HCDD (x-axis) and 1,2,3,6,7,8- HCDD (y-axis) in each breast milk sample. The Danish (red) and Finnish (blue) samples are completely separated into two distinct groups. In each country, the two chemicals show clear PC 1 linear correlations but with different slopes. 1,2,3,6,7,8-HCDD Denmark Finland ,2,3,4,7,8-HCDD The top most important chemicals in each of the two principal components: PC 1: 1,2,3,4,7,8- HCDD, PCBs (81,156, 157, 170, 180, 189, 194, 209), o.p - DDE. PC 2: 1,2,3,6,7,8- HCDD, 30 1,2,3,4,6,7,8- HepCDD, Mirex, 1,2,3,4,6,7,8- HepCDF, OCDD, PeBB, DD 25 estimated to be g I-TEQ year in 2002 (Finnish Ministry of the Environment, 2006). As the Danish estimate is imprecise, we are unable to assess in which country the emission is higher. In our dataset, seven different PCDD congeners were present including 2,3,7,8-TCDD, BDE- 154, 1,2,3,4,7,8- HCDD, PCB 49, Octachlorostyrene. Hexachlorobenzene and dieldrin are both organochlorine pesticides that were introduced at about the same time in the 1940s. In Denmark and Finland, this hexachlorobenzene was banned from use as a pesticide in 1993 and 1996 respectively and was totally banned in Krysiak- Baltyn et al. 2010

31 Scatter plots from the PLS (Partial Least Square): Danish and Finnish breast milk samples Healthy boy Cryptorchid boy Krysiak-Baltyn et al, 2012 IJA

32 3.69 geners in placenta were lower than the concentration found in the paired breast milk samples (n = 86) (Table 6), but there were significant correlations between the measurements, except for BDE-85 and BDE-138. The sum of all congeners in milk was 3.39 (95% CI, ) for boys with cryptorchidism and 3.15 (95% CI, ) for controls (p = 0.228), and in placenta 1.22 (95% CI, ) for boys with cryptorchidism Mita@u äidinmaidosta and 1.17 (95% CI, Al1stus PBDE:lle, dioksiineille ja PCB:lle on yhteydessä piilokiveksisyyteen Mita@u rasvakudoksesta Odds Ratio (95% CI) Breast milk (log) sum of BDE 47, 153, 99, 100, 26, and 66 (ng/g fat) 1 14 Sum of PBDEs Sum of 17 PCDD/Fs Sum of 37 PCBs Total TEq PBDE Dioksiini PCB PCB:n ja dioksiinien myrkkyekvivalenm 0 Denmark Finland Figure 1. Sum of the 7 most prevalent PBDEs in breast milk samples (BDEs 47, 153, 99, 100, 28, 66, 154, log-transformed values) from Denmark and Finland in boys with cryptorchidism (n = 62, blue) and healthy boys (n = 68, white). The box plot shows medians and interquartile ranges. Koskenniemi et al. submi@ed Main et al EHP Table 4. Seven less-prevalent PBDEs in breast milk sa

33 Yhteenveto Kivessyöpä saa alkunsa gonosyymen muuntumisesta spermatogoniaksi, jolloin solut GCNIS- soluiksi. Epidemiologista piilokiveksisyys, kivessyöpä ja huono siemennesteen laatu johtuisivat pienistä androgeenitasoista raskauden aikana. Näitä sairauksia yhdistävän al1stus ympäristön (an1- androgeenisille) hormonihäiritsijäkemikaaleille.

34 Kiitos mielenkiinnosta!

35 University of Turku Jorma Toppari Helena Virtanen Sergey Sadov Anne-Maarit Suomi Marko Kaleva Antti Perheentupa Jyrki Suominen Matti Vierula Johanna Järvi Wiwat Rodprasert Supported by EU, Envir. Reprod. Health, Expored, Eden, DEER Academy of Finland Pediatric Research Foundation Sigrid Juselius Foundation Turku University Hospital Danish Council for Strategic Research Finnish Cultural foundation Acknowledgments Rigshospitalet, Copenhagen Niels E. Skakkebæk Katharina M. Main Kirsten Boisen Ida Norgil Damgaard Niels Jorgensen Marlene Dalgaard Christine Wohlfahrt-Veje Anders Juul Anna-Maria Andersson Ewa Rajpert-De Meyts Inst. Health and Welfare, Kuopio Hannu Kiviranta Terttu Vartiainen

36 Jørgensen et al 2011 IJA