Çevresel  Etkilere  Maruziyet  ve  İlaçların  Sperm  Üretimi  Üzerine  Etkileri:  

Güncelleme  environmental  hazards  and  male  reproduction

Prof.Dr.Tülay İrez Biruni Üniversitesi Tıp Fakültesi

Histoloji ve Embriyoloji Anabilim dalı

Çevre  kirleticiler  ve  erkek  üreme  sistemi

•  1.Epidemiyolojik çalışmalar

•  2.Pestisidler,insektisidler,fungisidler

•  3. Plastikler ve endokrin bozucu kimyasallar

•  4. GDO

•  5. sigara ve tütün kullanımı

•  6. Hücresel etkiler

•  7. Sonuç

Sperm  sayımında  düşüş!

•  20 yıl önce Danimarkalı araştırıcılar 1940-1990 yılları arasında global olarak sperm sayımında %50 azalma saptadılar.

British Medical Journal.

•  Bunun ciddi olarak ele alınmasının gerekli olduğunu belirttiler

•  Neden olarak öne çıkanlar , seks hormonlarını taklit eden çevresel kimyasalların estrogen benzeri etkisi gösterildi.

Auger  et  al  1995 •  Studies show alarming sperm

count falls, but some distrust the figures

•  Latest French research reports a huge decline over a 17-year period, and numbers are a big cause for concern – if true

•  sperms of the human body, 1000x phase contrast

•  Debate

Decreasing sperm quality: a global problem?

•  Hiltrud Merzenich*, Hajo Zeeb and Maria Blettner

•  Institute of Medical Biostatistics, Epidemiology and Informatics, University

Medical Center of the Johannes Gutenberg University, Mainz

•  BMC Public Health 2010, 10:24 doi:10.1186/1471-2458-10-24

 

EMBO  Rep.  2012  May;  13(5):  398–403.Sperm  counts  and  fertility  in  men:  a  rocky  road  ahead    Richard  M  Sharpe  

 EDC  türü  kimyasallar  balıklarda  mineral  homeostasis’inde      olumsuz  etkiler  

yapmakta! •  Mar. Drugs 2014, 12(8), 4474-4494; doi:10.3390/md12084474

•  Review

•  Effects of Estrogens and Estrogenic Disrupting Compounds on Fish Mineralized Tissues

•  Patricia I. S. Pinto 1,†,* , Maria D. Estêvão 1,2,† •   and Deborah M. Power 1 •  1 CCMAR—Centre of Marine Sciences, University of Algarve, Campus de

Gambelas, Faro 8005-139, Portugal2 School of Health, University of Algarve, Av. Dr. Adelino da Palma Carlos, Faro 8000-510, Portugal† These authors contributed equally to this work.

•  * Author to whom correspondence should be addressed.

•  Received: 1 April 2014 / Revised: 17 July 2014 / Accepted: 30 July 2014 / Published: 15 August 2014

Possible consequences of germ line genetic damage

Michael Joffe Br Med Bull 2003;68:47-70

© The British Council 2003; all rights reserved

Ways in which genes and environment relate to each other.

Michael Joffe Br Med Bull 2003;68:47-70

© The British Council 2003; all rights reserved

Çevre  kirliliği  erkek  üreme  sistemine  olumsuz  etkiler  yapmaktadır

•  Artan bilimsel makaleler kimyasal ve fiziksel ajanların infertilite olgularının artışına dayanarak çevre kirleticiler açısından özel kimyasalların ve manyetik alanların varlığını işaret etti

•  Pestisidler

•  Phalat’lar

•  PCBs

•  Hava kirliliği

•  Trihalomethan’lar

•  Mobil telefonlar

Ø Endokrinbozucular •  DDT,  Dioxin,  PBDEs,  Phthalates

Ø Ağır  metaller •  kurşun  (sperm  sayısında  azalma)

Ø Organik  çözücüler •  Toluen,  benzen

Ø İlaçlar,  keyif  verici  bileşikler •  Alcohol

Reprodüktif  toksinler

Medikal  ilaçlar

Ø  Antibiotics (tetracylines)

Ø  Anticancer drugs

Ø  Anticonvulsants (Valproic Acid)

Ø  Lithium

Ø  Retinoids (Vitamin A)

Ø  Thalidomide

Ø  Diethylstilbestrol (DES)

Ø  Anticoagulants (Warfarin)

Alışkanlık  oluşturan  maddeler

Ø  Alcohol (ethanol)

Ø  Tobacco

Ø  Cocaine

Ø  Solvent abuse

Classes  Of  Pesticides

Ø  Insecticides (kill insects)

•  Organochlorines

•  Organophosphates

•  Carbamates

•  Synthetic Pyrethroids

Ø  Herbicides (kill plants)

Ø  Rodenticides (kill rodents)

Ø  Fungicides (kill fungus)

Ø  Fumigants (kill whatever)

DBCP  (dibromochloropropane)  1977  de  şiddetli  sperm  toksik  etkisi  gösterildi.  nematocide  

dibromochloropropane  (DBCP)    

•  2009 da destekleyen çalışmalar yayınlandı

•  JOANNA JUREWICZ , WOJCIECH HANKE, MICHAŁ RADWAN , and JENS PETER BONDE

International Journal of

Occupational Medicine and

Environmental Health 2009;22(4):305–329 DOI 10.2478/

v10001-009-0036-1

 Nematocide  dibromochloropropane  (DBCP)  (1970’s) o  Azoospermia

o  Oligospermia

o  Increased plasma LH, FSH

o  Atrophy seminiferous tubular epithelium

•  Human testes affected

•  Sim in lab animals, but to lesser extent

o  Extrapolation from animal to human unfortunate

o  Recovery w/in 18-21 mos

Pestisidlerin  endokrin  bozucu  etkileri

•  Arjantinli iftçilerde pestiside maruz kalan kişilerde yüksek E2 ve düşük LH konsantrasyonu saptandı.

•  Japonyada pestisid işçilerinde kış aylarında serum testosteron düzeyinin yaz aylarına göre daha yüksek olduğu gözlendi(p < 0.05), FSH ve LH konsantrasyonlarında farklılık görülmedi.

•  Sperm sayısı ve canlılığı ile ilgili çalışmalarda benzer sonuçlar bulunduğu halde sperm motilitesinin pestisid işçilerinde daha düşük (p < 0.05), e hızlı hareketli spermler de daha düşük yüzdelerde olduğu görüldü (p = 0.06).

Endokrin  bozucu  kimyasallar  (EDCs) •  Sperm kalitesi—pek çok çalışma kaliteyi düşürdüğü konusunda

hemfikir •  Fertilite—fertileyi olumsuz etkilediği, abort oranlarını arttırdığını

göstermiştir •  prenatal uygulamada erkek seks organlarında anomaliler

görülmüştür. •  Erken puberte •  Bazı kanser grupları ile ilişki

o  Testicular kanser insidansında artış (1973 den 1999’a ) •  kafkasya: 51.8% •  Afrikalı-Amerikalı: 49.4%

o  Meme kanserinde artış •  Kafkasyalı: 27.9% •  Afrikalı-Amerikalı: 34.8%

o  14 yaş ve altı çocuklarda beyin kanserinde artış •  50.2%

Endocrine  disruptors  (e.g.,  polychlorinated  biphenyls  [PCBs],  dichlorodiphenyl-­‐‑trichloroethane  [DDT],  dioxin,  and  

some  pesticides)  are  estrogen-­‐‑like  and  anti-­‐‑androgenic  chemicals  in  the  environment

•  Doğal hormonları taklit

•  Regülatör sistemleri değiştirir

•  Erkek üreme sistemi üzerinde ciddi

tehlike

•  Testis,prostat kanseri

•  İnmemiş testis,

•  Hypospadias

•  Hipofiz ve tiroid glandlar üzerine

negatif etki

Pestisidler  reproduktif  hücrelerde  estrogenik  veya  androgenik  etki  

oluşturmakta •  A M Soto, K L Chung, and C Sonnenschein

•  Environ Health Perspect. 1994 Apr; 102(4): 380–383.

•  The pesticides endosulfan, toxaphene, and dieldrin have estrogenic effects on human estrogen-sensitive cells

•  Helle Raun Andersena, Anne Marie Vinggaardb, Thomas Høj Rasmussena, Irene Marianne Gjermandsenc, Eva Cecilie Bonefeld-Jørgensenc

•  Effects of Currently Used Pesticides in Assays for Estrogenicity, Androgenicity, and Aromatase Activity in Vitro

•  Toxicology and Applied Pharmacology

•  Volume 179, Issue 1, 15 February 2002, Pages 1–12

Endokrin  fonksiyon  bozuklukları •  Pesticide Exposure and Endocrine Dysfunction in the Cotton Crop

Agricultural Workers of Southern Punjab, Pakistan •  Asia Pac J Public Health March 1, 2013 25: 181-191

•  Pesticide soil contamination mainly affects earthworm male reproductive parameters

Eduardo Bustos-Obregn, Roger Iziga Goicochea

Biology of Reproduction Unit. Program of Morphology, ICBM Faculty of Medicine, University of Chile, Santiago, Chile

Asian J Androl 2002 Sep; 4: 195-199

  •  [Effects of occupational exposure to pesticides on semen quality of

workers in an agricultural community of Merida state, Venezuela].

•  Miranda-Contreras L, Cruz I, Osuna JA, Gómez-Pérez R, Berrueta L, Salmen S, Colmenares M, Barreto S, Balza A, Morales Y, Zavala L, Labarca E, García N,Sanchez B, Contreras CA, Andrade H.

•  Invest Clin. 2015 Jun;56(2):123-36

•  Significant alterations of some semen parameters in the exposed group were found, such as: decreases in sperm concentration, slow progressive motility and sperm membrane integrity; at the same time, increases in eosin Y positive and sperm DNA fragmentation index.

1998-­‐‑2006  Multiple  herbicides,  insecticides  and/or  fungicides •  Bigelow (1998) 55 exposed; 319 unexposed Unspecified pesticides Mean semen volume (4.5 versus 3.3 ml)

& tapering head defects significantly higher in exposed group

•  Larsen (1998) 161 farm sprayers; 87 non-sprayers Hs, Is, Fs Non-significant changes found in sperm morphology, vitality & motility between 2 groups

•  Tielemans (1999) 43 exposed; 856 unexposed Hs, Is, Fs Exposure to pesticides was not associated with changes in semen quality

•  Abell (2000) 13 high, 64 intermediate, 44 low exposure >60 pesticides: Hs, Is, Fs Sperm concentration (36 versus 87 × 106/ml) & proportion normal spermatozoa (61% versus 71%) significantly lower in high exposure group

•  Padungtod (2000) 32 OP exposed workers; 43 controls Is & OPs Significant reductions in sperm concentration (mean = 43 versus 75 × 106/ml) & % motility (47 versus 57) in high exposure group

•  Oliva (2001) 40 exposed, 80 non-exposed Hs, Is, Fs Exposure associated with increased seminal volume (OR 2.8, CI 1.2–6.6); & lower sperm concentration (OR 3.0, CI 1.2–7.4) output (OR 2.7, CI 1.1–6.7) & motility (OR 4.5, CI 1.8–11.5)

•  Swan (2003) 50 low semen parameters; 36 within normal limits Al, IMPY, At, M, 2,4-D & others Odds for low semen quality higher in men exposed to Al (OR 30.0, CI 4.3–210) At (OR 11.3, CI 1.3–98.9) & IMPY (OR 16.7, CI 2.8–98.0)

•  Kamijima (2004) 18 pesticide sprayers; 18 controls Is Percent of slow progressive (15.6 versus 8.8) & non-progressive motile sperm (5.9 versus 2.5) twice as high in the sprayers spraying in summer

•  Sanchez-Pena (2004) 33 men selected from 227 workers Hs, Is, Fs No significant association between semen quality & DETP or DAP

•  Yucra (2006) 31 pesticide sprayers; 80 unexposed OPs Sprayers had significantly lower seminal volume (2.1 versus 2.7 ml), percentage motility (58.6 versus 71.0), percent normal morphology grade A (18.7 versus 28.3) & grade A+B (53.6 versus 64.2)

Single  pesticides •  Single pesticides

•  Lerda (1991) 32 farm sprayers; 25 controls 2,4-D Farm sprayers had significantly lower semen concentration: 49.0 versus 101.6 × 106/ml in controls

•  Meeker (2004a) 272 recruited from an infertility clinic Carbaryl, Chlorpyrifos 1N associated with lower sperm concentration (OR 4.2, CI 1.4–12.6) & motility (OR 2.4, CI 1.2–4.5)

•  Lifeng (2006) 32 pesticide plant workers; 68 non-exposed controls Fenvalerate Sperm count significantly lower in exposed group (GM

= 54.0 versus 89.5 106/ml)

DDT  and  metabolites

•  Dallinga (2002) 31 with normal PMSC; 34 men below normal PMSC PCBs, HCB, p,p'-DDE & p,p'-DDT Correlations between OC metabolites in blood & sperm count (R2 = 0.14; P = 0.04) & PMSC (R2 = 0.17; P = 0.02) in normal semen quality group

•  Hauser (2002) 29 cases; 18 men with normal semen parameters PCBs & p,p'-DDE General trends of an association between PCBs & p,p'-DDE & abnormal motility, sperm concentration & morphology; no statistical analyses due to small sample size

•  Hauser (2003) 212 partners of subfertile couples PCBs, p,p'-DDE Significant association for PCBs but limited evidence of association between p,p'-DDE & motility

•  Dalvie (2004) 27 unexposed; 27 highly-exposed DDT Serum p,p′-DDT negatively associated with sperm count 106/ml (adjusted R2 = 0.05 P = 0.04)

•  Pant (2004) 45 fertile & 45 infertile men HCH & DDT High levels of pesticides observed in semen of infertile men

•  Rignell-Hydbom (2004) 195 Swedish fishermen p,p'-DDE, CB-153 Inverse but non statistically significant association between serum levels of CB-153 & sperm motility

•  Magnusdottir (2005) 25 with subfertility; 47 with normal semen quality PCBs, p,p'-DDE No difference in the level of OCs between the groups

Organophosphate,  carbamate •  Occupational exposure to organophosphate and carbamate

pesticides affects sperm chromatin integrity and reproductive hormone levels among Venezuelan farm workers.

•  Miranda-Contreras L1, Gómez-Pérez R, Rojas G, Cruz I, Berrueta L, Salmen S, Colmenares M, Barreto S, Balza A, Zavala L, Morales Y, Molina Y, Valeri L,Contreras CA, Osuna JA.

•  J Occup Health. 2013;55(3):195-203. Epub 2013 Feb 27.

Sperm  parametrelerinde  düşüş  ve  pestisid  ilişkisi

•  Toxicology. 2013 May 10;307:66-73. doi: 10.1016/j.tox.2013.02.005. Epub 2013 Feb 22.

•  Environmental and occupational pesticide exposure and human sperm parameters: a systematic review.

•  Martenies SE, Perry MJ.

•  Specific pesticides targeted for study included dichlorodiphenyltrichloroethane (DDT), hexachlorocyclohexane (HCH), and abamectin.

hMp://web.bryant.edu/~dlm1/sc372/readings/toxicology/endocrinedisrupter.jpg

• Some chemicals mimic a natural hormone, fooling the body into

over-responding to the stimulus (e.g., a growth hormone that

results in increased muscle mass), or responding at inappropriate

times (e.g., producing insulin when

it is not needed). • block the effects of a hormone

from certain receptors (e.g. growth

hormones required for normal development).

• directly stimulate or inhibit the endocrine system and cause

overproduction or underproduction

of hormones • Epa.gov

 

Konstantin  Svechnikov,  Jan-­‐‑Bernd  Stukenborg,  Iuliia  Savchuck,  Olle  Söder  

Asian  J.of  Andrology  2014,16,50-­‐‑59 •  Summary diagram of the putative mechanisms underlying

the development of reproductive disorders in human male fetuses. Different classes of endocrine-disrupting chemicals (EDCs) inhibit the production of androgens and insulin-like factor 3 (Insl3) by fetal Leydig cells (FLCs) in the sensitive androgen-dependent period of male reproductive organ development.

•  Under-masculinization disturbs the proper formation and growth of the penis, increasing the risk of developing hypospadias and micropenis.

•  A lack of Insl3 alters the normal testis descent, leading to cryptorchidism.

•  EDCs can impair Sertoli cell (SC) differentiation from their progenitors and alter the proliferation of gonocytes that may lead to poor semen quality in postnatal life.

•  EDCs may also directly impair the development of the reproductive organs by antiandrogenic or estrogen-mediated mechanisms and affect the methylation and/or acetylation status of the fetal testicular cells, which may create an abnormal genetic background and an increased risk of testicular cancer in postnatal life.

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         

Targeting  testis-­‐‑specific  proteins  to  inhibit  spermatogenesis:  lesson  from  endocrine  disrupting  chemicals HT  Wan,  Dolores  D  Mruk,  Chris  KC  Wong,  and  C  Yan  Cheng,  Expert  Opin  Ther  Targets.  2013  Jul;  17(7):  839–855.

PFC  bileşikleri,kurşun  ve  kadmium  LH  reseptor  gen  ekspresyonunda  down  

regülasyon  oluşturmakta  Testosteron  düzeyinde  azalma  gözlenmektedir!

•  Leydig cell steroidogenesis is one of the primary targets of EDCs. Perfluorinated compounds (PFCs), such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perflorododecanoic acid (PFDOA), perfluorodecanoic acid (PFDA) and perfluoronanoic acid (PFNA) were shown to reduce serum testosterone level in rodents and also in spent medium of Leydig cells cultured in vitro . PFOS was also shown to down-regulate LH receptor gene expression without affecting pituitary LH mRNA levels in adult mice, suggesting disruptive effects of PFOS on LH receptor expression but not LH per se . Similar effects were also reported in cadmium and lead treated rodents.

•  HT Wan, Dolores D Mruk, Chris KC Wong, and C Yan Cheng, Expert Opin Ther Targets. 2013 Jul; 17(7): 839–855.

Schematic diagram depicting several key steps in steroid hormone action that may be sensitive to disruption by

environmental chemicals: synthesis and secretion of steroids hormones [EA] from the gonadal cells; binding affinity

of the EA for the SHBG protein; diffusion into the cell; diffusion into the perinuclear region; binding the receptor;

conformational change of the receptor (R) which forms homodimers; formation of a transcriptional complex from

homodimers; which binds to specific sequences on the DNA of hormone-dependent genes, known as HRE;

transportation of mRNA into the cytoplasm; synthesis of proteins; alteration of liver function, either increasing or

decreasing metabolism of the hormone *Possible key stepsin steroid hormone action sensitive to EDCs.

D. Caserta et al. Hum. Reprod. Update 2008;14:59-72

© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction

and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Çevresel  toksitite  alarmı •  Environmental toxins: alarming impacts of pesticides on male fertility. •  Sengupta P1, Banerjee R2. Hum Exp Toxicol. 2014 Oct;33(10):1017-39. doi: 10.1177/0960327113515504. Epub 2013 Dec 17. •  Abstract •  This review comprehensively summarizes the effects of more than 15 mostly

used pesticides on male reproductive physiology, as recent experimental and epidemiological research have indicated their alarming impact on overall human health. Mechanisms have described that pesticide exposure damages spermatozoa, alter Sertoli or Leydig cell function, both in vitro and in vivo and thus affects semen quality. But, the literature suggests a need for more intricate research in those pesticides that are defined as mutagens or carcinogens and directly affect the hypothalamic-pituitary-gonadal axis. This literature review also proposes specific solutions to overcome these health effects.

Leukemia  internasyonal  konsorsiyumu  raporu  2014

•  Parental occupational pesticide exposure and the risk of childhood leukemia in the offspring: findings from the childhood leukemia international consortium.

•  Bailey HD1, Fritschi L, Infante-Rivard C, Glass DC, Miligi L, Dockerty JD, Lightfoot T, Clavel J, Roman E, Spector LG, Kaatsch P, Metayer C, Magnani C, Milne E,Polychronopoulou S, Simpson J, Rudant J, Sidi V, Rondelli R, Orsi L, Kang AY, Petridou E, Schüz J.

•  Int J Cancer. 2014 Nov 1;135(9):2157-72. doi: 10.1002/ijc.28854. Epub 2014 Apr 4

Leukemia  international  consortium  reports

•  Abstract •  Maternal occupational pesticide exposure during pregnancy and/or paternal occupational

pesticide exposure around conception have been suggested to increase risk of leukemia in the offspring. With a view to providing insight in this area we pooled individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium (CLIC). Occupational data were harmonized to a compatible format. Pooled individual analyses were undertaken using unconditional logistic regression. Using exposure data from mothers of 8,236 cases, and 14,850 controls, and from fathers of 8,169 cases and 14,201 controls the odds ratio (OR) for maternal exposure during pregnancy and the risk of acute lymphoblastic leukemia (ALL) was 1.01 [95% confidence interval (CI) 0.78, 1.30] and for paternal exposure around conception 1.20 (95% 1.06, 1.38). For acute myeloid leukemia (AML), the OR for maternal exposure during pregnancy was 1.94 (CI 1.19, 3.18) and for paternal exposure around conception 0.91 (CI 0.66, 1.24.) based on data from 1,329 case and 12,141 control mothers, and 1,231 case and 11,383 control fathers.

•  Our finding of a significantly increased risk of AML in the offspring with maternal exposure to pesticides during pregnancy is consistent with previous reports. We also found a slight increase in risk of ALL with paternal exposure around conception which appeared to be more evident in children diagnosed at the age of 5 years or more and those with T cell ALL which raises interesting questions on possible mechanisms.

Biomarker’lerin  belirlenmesi •  Chemosphere. 2015 Nov;139:91-108. doi: 10.1016/j.chemosphere.2015.05.082. Epub 2015 Jun 10. •  Occurrence of biomarkers of pesticide exposure in non-invasive human specimens. •  Yusa V1, Millet M2, Coscolla C3, Pardo O4, Roca M3.

•  Abstract •  Biomonitoring has been used in many types of investigations, including national programmes and

epidemiological studies, to explore the occurrence of biomarkers of pesticide exposure in the general population or relevant groups. This review discusses recent studies that measure levels of biomarkers of pesticide exposure in non-invasive human specimens such as urine, breast milk, meconium and hair. Specific and non-specific metabolites of organophosphate and pyrethroid insecticides have been widely investigated in urine, where some of the suitable biomarkers present rates of detection higher than 80%, which stand for an ongoing chronic exposure to traces of these chemicals. Hair is a promising emerging matrix, but some issues on its suitability and the biological relevance needs further research. Breast milk was used in research investigations focused mainly on legacy pesticides, which provide useful information about time trends.

•  A widely used biochemical biomarker, cholinesterase depression, measures exposure to organophosphorus insecticides. Techniques that measure DNA damage (e.g., detection of DNA adducts) provide a powerful tool in measuring environmental effects

Dezenfektanlar •  Ev ve hastane sterilizasyonlarında kullanılan ajanlar •  örnekler

o Alkoller

o Chlorhexidine

o Hypochlorite

o  Iodines

o  Phenols

o  Pine oil

İçme  suyu  dezenfektanları •  Çeşme sularında Trihalomethan

•  Trihalomethan’lar (THMs) sularda dezenfeksiyon sonrası oluşmakta klorin ile tabii organik materyallerin oluşturduğu bileşikler THMs chloroform, bromoform, chlorodibromomethane, bromodichloromethane,. Dermal absorbsiyon el yıkama , banyo, inhalasyon yolu ile vücuda girer.

Hayvan  çalışmaları  trihalometanların  erkek  üreme  sistemi  

üzerinde  olumsuz  etkilerini  göstermektedir! •  . Evaluation of exposure to trihalomethanes in tap water and semen quality: a prospective study in

Wuhan, China.

Zeng Q1, Chen YZ1, Xu L1, Chen HX1, Luo Y1, Li M1, Yue J2, Liu AL1, Li YF3, Lu WQ4. Author information

Abstract Trihalomethanes (THMs) have been demonstrated to adversely affect male reproductive health in animals,

but the evidence in humans is limited. The study aimed to examine the association between THM exposure

and semen quality in a Chinese population. We recruited 324 men from the same water supply district in Wuhan, China between April 2011 and May 2012. Exposure to THMs was evaluated based on their

concentrations in tap water measured within 90 days preceding semen collection, the uptake factors of

THMs and personal information on ingestion and showering/bathing. We found that TTHM [sum of chloroform (TCM) and brominated THMs (Br-THMs)], TCM and Br-THM uptakes via ingestion were

associated with significant or suggestive decreasing trends in sperm concentration (P for trend=0.01, 0.03 and 0.05, respectively) and sperm count (P for trend=0.02, 0.05 and 0.09,

respectively). Our results suggest that THM exposure via ingestion may adversely affect semen

quality. Copyright © 2014. Published by Elsevier Inc.

Hava  kirliliği •  Sülfür dioksit (SO2), nitrogen oksit

(NOx), partiküller (PM) ve ozon(O3 ). •  Yüksek oranda cinsiyet

kromozomlarında anormallikler •  Organochlorin , dioksinler ve

polychlorinated biphenyller •  Hayvan çalışmaları negatif etkileri

göstermektedir •  Pre- and postnatal exposure to ambient levels

of urban particulate matter (PM(2.5) affects mice spermatogenesis.

•  Pires A, de Melo EN, Mauad T, Nascimento Saldiva PH, de Siqueira Bueno HM.

•  Inhal Toxicol. 2011 Mar;23(4):237-45. doi: 10.3109/08958378.2011.563508.

Francesca Cimmino2,Giancarmelo Puca2, Annamaria Colao1 and Gaetano Lombardi1

Hum. Reprod. (2003) 18 (5): 1055-1061.

doi: 10.1093/humrep/deg226

Traffic pollutants affect fertility in men Table I.

Clinical and endocrine parameters in 85 men occupationally exposed to environmental pollutants compared

with 85 control men randomly selected

Controls

Study group P-­‐value

Mean ±

SE Range

Mean ±

SE Range

Age (years)

39.6 ±

0.7 29–53

38.6 ±

0.8 23–62 NS

Married [no. (%)] 63 (74.1) –

71 (83.5) – NSa

Children (no.)b 2.0 ± 0.1 0–4

1.8 ± 0.1 0–4 NS

TTP (mos.)b 8.1 ± 0.4 0–15

15 ± 1.6 0–60

<

0.0001

Serum FSH (IU/l) 3.2 ± 0.2 0.9–6.3

4.1 ± 0.3

0.7–

13.5 < 0.05

Serum LH (IU/l) 2.8 ± 0.1 0.9–5.4

2.8 ± 0.2 0.7–8.9 NS

Serum testosterone

(µg/l) 4.7 ± 0.2

2.9–

10.8

4.8 ± 0.2 2.3–9.2 NS aχ2-­‐test.

bOnly married men.

TTP = time to induce the first pregnancy; NS = not significant.

. Gynecol Endocrinol. 2015 Jan;31(1):7-13. doi: 10.3109/09513590.2014.958992. Epub 2014 Sep 12 Impact of air pollution on fertility: a systematic review.

Frutos V1, González-Comadrán M, Solà I, Jacquemin B, Carreras R, Checa Vizcaíno MA. Author information

Abstract Air pollution has gained considerable interest because of the multiple adverse effects reported on human health,

although its impact on fertility remains unclear. A systematic search was performed to evaluate the impact

of air pollutants on fertility. Controlled trials and observational studies assessing animal model and epidemiological model were included. Occupational exposure and semen quality studies were not considered. Outcomes of interest

included live birth, miscarriage, clinical pregnancy, implantation, and embryo quality. Ten studies were included and

divided into two groups: animal studies and human epidemiological studies including the general population as well as women undergoing in vitro fertilization and embryo transfer (IVF/ET). Results from this systematic review

suggest a significant impact of air pollution on miscarriage and clinical pregnancy rates in the general population, whereas among subfertile patients certain air pollutants seem to exert a greater impact on fertility outcomes,

including miscarriage and live birth rates. Besides, studies in mammals observed a clear detrimental effect on

fertility outcomes associated to airpollutants at high concentration. The lack of prospective studies evaluating the effect of air pollution exposure in terms of live birth constitutes an important limitation in this review. Thus, further

studies are needed to confirm these findings. KEYWORDS:

Air pollution; diesel exhaust particles; fertility; live birth; miscarriage; nitrogen dioxide; particulate matter

•  Environmental car exhaust pollution damages human sperm chromatin and DNA.

•  Calogero AE1, La Vignera S, Condorelli RA, Perdichizzi A, Valenti D, Asero P, Carbone U, Boggia B, De Rosa N, Lombardi G, D'Agata R, Vicari LO, Vicari E, De Rosa M

•  J Endocrinol Invest. 2011 Jun;34(6):e139-43. doi: 10.3275/7298. Epub 2010 Oct 15

•  This study showed that car exhaust exposure has a genotoxic effect on human spermatozoa. This may be of relevant importance not only for the reproductive performance of the men exposed, but also for the offspring health.

BPA •  Erkek üreme sistemi üzerine etki,

•  Farelerde BPA günlük sperm üretimini azaltmakta,

•  Bir çalışmada, BPA oral dozu 20 g/kg testis ağırlıklarında azalma ve günlük sperm üretiminde anlamlı düşüş sağlamakta (Sakaue et al., 2001).

Ann  Endocrinol  (Paris).  2013  Jul;74(3):211-­‐‑20.  doi:  10.1016/j.ando.2013.04.002.  

Epub  2013  Jun  21 •  Bisphenol A: an endocrine and metabolic disruptor. •  Fenichel P1, Chevalier N, Brucker-Davis F. •  Abstract •  Bisphenol A (BPA), initially designed, like diethylstilbestrol, as a synthetic estrogen, has been rapidly

and widely used for its cross-linking properties in the manufacture of polycarbonate plastics and epoxy resins. Because of incomplete polymerization and degradation of the polymers by exposure to higher than usual temperatures, BPA leaches out from food and beverage containers, as well as from dental sealants. In humans, free active unconjugated BPA is metabolized by rapid glucurono- or sulfo-conjugation and eliminated via renal clearance. However, exposure to environmental nanomolar concentrations of BPA is ubiquitous and continuous via different routes: oral, air, skin. In rodents, fetal and perinatal exposure to such environmentally relevant doses of BPA has been shown to affect the brain, liver, gut, adipose tissue, endocrine pancreas, mammary gland and reproductive tract and function. Similar concentrations are also able in vitro to impact human malignant breast, prostate, male germ or adipocyte celllines (with a promoting effect and by interfering with chemotherapy drugs), or to stimulate pancreatic β cell insulin secretion. High levels of BPA have recently been correlated with obesity, diabetes, cardiovascular diseases, polycystic ovarian disease or low sperm count. However, before the real impact of BPA on human health can be clearly assessed, prospective longitudinal epidemiological studies are needed as well as characterization of selective biomarkers to verify long-term exposure and selective imprinting.

Perinatal  Exposure  to  Environmentally  Relevant  Levels  of  Bisphenol  A  Decreases  Fertility  and  Fecundity  in  CD-­‐‑1  Mice  

Nicolas  J.  Cabaton1*,  Perinaaz  R.  Wadia1*,  Beverly  S.  Rubin1,  Daniel  Zalko2,  Cheryl  M.  Schaeberle1,  Michael  H.  Askenase1,  Jennifer  L.  Gadbois1,  Andrew  P.  

Tharp1,  Gregory  S.  Whis1,  Carlos  Sonnenschein1,  Ana  M.  Siron  Environ  Health  Perspect  119:547-­‐‑552  (2011).  

•  Major targets of BPA, NP and MEHP in a mammalian testis.Bisphenol A (BPA), 4-nonylphenol (NP) and di(2-ethylhexyl) phthalate (DEHP) disrupt spermatogenesis at different levels. They lower intratesticular and plasma testosterone (T) by affecting Leydig cells, resulting in decreased spermatogenesis. In addition, in vitro and in vivo studies show that Sertoli cells (SC) are primary targets of these compounds, affecting their metabolism, protein expression and morphology. BPA induces spermatogonium (SP), pachytene spermatocyte (PC) and preleptotene spermatocyte (PlC) apoptosis by affecting SC. The blood-testis barrier (BTB), which separates the adluminal compartment from the basal compartment within seminiferous tubules, ectoplasmic specializations (ES), which maintain attached elongated spermatids (S) to SC, and gap junctions (GJ) are disrupted by EDs, producing sloughing and apoptosis of germ cells.

EDs  molecules  and  apoptosis •  Model of the effects of EDs on

Sertoli-germ cell interaction and germ cell apoptosis and sloughing. Depiction of a model of para/juxtacrine signaling events between germ cells (GC) and Sertoli cells during apoptosis induced by endocrine disruptors. Dotted lines indicate an unknown mechanism. Triangles represent EDs molecules.

Int J Environ Res Public Health. 2014 Jul; 11(7): 7537–7561.

Published online 2014 Jul 22. doi: 10.3390/ijerph110707537

Bisphenol-A: Epigenetic Reprogramming

and Effects on Reproduction and Behavior

Guergana Mileva,, Stephanie L. Baker, Anne T.M. Konkle, and Catherine Bielajew

• 

•  Models showing the roles of ERs, MLLs and other ER-coregulators during BPA and DES mediated endocrine disruption of HOTAIR. Steroidogenic EDCs like BPA and DES binds to ERs (ERα and ERβ), in a similar fashion to estradiol. Activated ERs ...

•  Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo

•  Arunoday Bhan,1 Imran Hussain,1 Khairul I. Ansari,1 Samara A. M. Bobzean,2 Linda I. Perrotti,2 and Subhrangsu S. Mandal1,*

•  BPA and DES exposure alters the epigenetic programming of the HOTAIR promoters

Agrobacterium  is  bacteria  that  uses  a  Horizontal  gene  transfer  

(HGT).  HGT  is  the  transfer  of  DNA  between  different  genomes •  [Pop up: A genome is the

complete set of genetic material present in an organism]. HGT can occur in bacteria through transformation, conjugation and Transduction. However, it is also possible for HGT to occur between eukaryotes and bacteria though the mechanism for this transfer is not well understood.

Vitamine  A  rich  golden  rice

Sigara  ve  sperm  konsantrasyonu  

1.infertil  sigara  içen,2.  infertil  sigara  içmeyen,3.  fertil  sigara  içen  4.fertil  sigara  içmeyen

•  Pınar Altıner, Tülay İrez

Semendeki  Kurşun  Konsantrasyonu

Cep  telefonları  ve  sperm  kalitesi •  Mobile Phone Radiation Induces Reactive Oxygen Species Production and DNA Damage in Human Spermatozoa In Vitro •  Geoffry N. De Iuliis, Rhiannon J. Newey, Bruce V. King, R. John Aitken Published: July 31, 2009DOI: 10.1371/journal.pone.0006446

•  Effect of mobile telephones on sperm quality: a systematic review and meta-analysis. •  Review articleAdams JA, et al. Environ Int. 2014.

•  Abstract •  Mobile phones are owned by most of the adult population worldwide. Radio-frequency electromagnetic radiation (RF-EMR) from

these devices could potentially affect sperm development and function. Around 14% of couples in high- and middle-income countries have difficulty conceiving, and there are unexplained declines in semen quality reported in several countries. Given the ubiquity of mobile phone use, the potential role of this environmental exposure needs to be clarified. A systematic review was therefore conducted, followed by meta-analysis using random effects models, to determine whether exposure to RF-EMR emitted from mobile phones affects human sperm quality. Participants were from fertility clinic and research centres. The sperm quality outcome measures were motility, viability and concentration, which are the parameters most frequently used in clinical settings to assess fertility. We used ten studies in the meta-analysis, including 1492 samples. Exposure to mobile phones was associated with reduced sperm motility (mean difference -8.1% (95% CI -13.1, -3.2)) and viability (mean difference -9.1% (95% CI -18.4, 0.2)), but the effects on concentration were more equivocal. The results were consistent across experimental in vitro and observational in vivo studies. We conclude that pooled results from in vitro and in vivo studies suggest that mobile phone exposure negatively affects sperm quality. Further study is required to determine the full clinical implications for both sub-fertile men and the general population.

•  Copyright © 2014. Published by Elsevier Ltd.

Sonuçlar: •  Endokrin bozucu kimyasallar pestisid ve temizlik ve dezenfeksiyon amacı ile

kullanılan solusyonları içermektedir, plastiklerden geçen Bisfenol A da endokrin bozucu kimyasal olarak davranmakta DDT/Dichlorodiphenyldichloroethylene [DDE], ethylenedibromide, organophosphat’lar sperm konsantrasyonlarını düşürmekte, sperm motilitesi üzerinde olumsuz etkiler ortaya çıkarmaktadır.

•  GDO içeren sebze ve meyvelerin, tohumların gelecekte insan sağlığını ciddi etkileyeceği ve üreme sistemi üzerinde olumsuz etkiler oluşturacağı ve infertilite ile birlikte kanser olgularının artışı yaşamı tehdit eder noktaya ulaşmıştır.

•  Manyetik alanlar ve cep telefonlarının erkeklerde sperm kalitesi üzerinde olumsuz etkileri yayınlanmaya başlamıştır.

Bu  konuda  yapılması  gerekli  acil  çalışmalar *    İnsan  üreme  sistemi  ve  hücreleri  üzerinde  temel  araştırmalar   *    Dağılımı  metabolizması  ve  birikme  yolları *    Mobilizasyonu  degredasyonu  ,  değişik  yaşam  sajalarında *    Davranışlar  üzerine  etkileri   *    In  vitro  reseptör  bağlanma  çalışmaları *    fizyolojisi *    Gelişen  germ  hücreleri  üzerindeki  etkileri   *    Etkilediği  genlerin  karakterizasyonu *    Duyarlı  ve  ucuz  araştırma  yöntemlerinin  geliştirilmesi   *    Detaylı  farmakodinamik/kinetik  çalışmaların  geliştirilmesi