Conferencia Dr. Carrasco


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Conferencia Dr. Carrasco

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Conferencia Dr. Carrasco

  1. 1. “This time results of anunlimited license granted totechnology” and....“constitute the perfect crimeto kill reality” Jean BaudrillardAndres E. CarrascoLaboratorio Embriologia MolecularFacultad de Medicina UBA-CONICET
  2. 2. Argentina and agrotoxics and Territorial conflicts
  3. 3. Elfuturo:P.A.N
  4. 4. Soy in ArgentinaExtension: 20.000.000 Ha.GBH: 200.000.000 liters year , (Paraguay GBH 8 liters year)Population living in the territory 10.000.000 people.70 % of the effects are by inhalation.
  5. 5. Increasing of use of plaguicides 1999-2009
  6. 6. Preliminary epidemiological humans studies in Argentina
  7. 7. Birth prevalence of 27 selected congenital anomalies in 7 geographicregions of Argentina ,Campaña et al (ECLAMC group). Arch Argent. Pediatr. 108 (5) 409-417, 2010Out of the 27 congenital anomalies analyzed, 14 showed a frequencysignificatively higher in one or more regionsCentro spina bifida, microtia, cleft lip with cleft palate, polycystic kidney,postaxial polydactyly and Down Syndrome,Northest omphalocele, gastroschisis, cleft lip with and without cleft palate,anorectal atresia/stenosis, indeterminate sex, preaxial polydatily and pectoralagenesis,Patagonia cleft lip with cleft palate.Cuyo postaxial polydactyly,Pampa, severe hypospadias
  8. 8. CORDOBA
  9. 9. Obstetric and Neonatology Hospital, Cordoba Univ, (Dra. Trombotto) On 111.000 newborns, CRANEOFACIAL , GASTROSCHISIS, LIMB DEFORMITIES Incidence of MCM (not due to genetics or familiar bias) 1991: 16.2 %o newborns. 2003 : 37.1 %o newborns.
  10. 10. Ituzango, Cordoba. RED DOTS: CANCER CASES
  11. 11. Chaco, Argentina Departamento Bermejo Puerto Eva Perón General Vedia Puerto BermejoLA LEONESA Las Palmas Isla del Cerrito
  12. 12. La Leonesa, Dept. Rio Bermejo, Chaco Población Menores Casos Esperados Casos Incidencia Municipio Total de 15 años Ca Infantil - por año Registrados años 2001 - 2001 1995: 1 caso 1990-1999 1997: 0,41 casos por año 2000: 1 “ 1 ” 0,2 casos/año – 1 caso/60meses 300%   La 10.067 2960 ( 1 caso c/ 24- 36 2003: 2 “ Leonesa 2000-2009 meses) 2004: 1 “ 2008: 1 “ 0,6 casos/año – 1 caso/20 2009: 1 “ meses 1990-1999 0,2 casos/año 0,3 casos por año 1993: 1 “ 1 caso/60 meses Las 6593 2146 ( 1 caso c/ 36-42 1995: 1 “ Palmas 2000-2009 meses) 2006: 1 “ 0,1 caso/año 1 caso/ 120 meses 1990-1999 0,1 caso/año 0,09 casos x año Puerto 1995: 1 caso 1 caso/20 meses 1832 652 ( 1 caso c/ 96 Bermejo 2008: 1 “ 2000-2009 años) 0,1 caso/año 1 caso/120 meses
  13. 13. Malformations % in total live newbornsAño N /year Live born Incidency (malformations *10000/ live born )1997 46 malformacions 24030 (live born 1997) 19,1 /10.0002001 60 malformacions 21339 (live born 2001) 28,1 /10.0002008 186 malformacions 21.808 (live born 2008) 85,3 /10.000 400%  en  los   ul,mos  10  años      
  14. 14. Benitez Leite et al, Rev Ped. Paraguay (2009) 139 newborns were analyzed. Where founded 52 malformations associated to exposure to agrotoxics (plus 34 death fetus).In Roque Saenz Peña, Chaco, Argentine.In 4 years, over 4255 of newborns, 157malformations were detected (average 3.6%)
  16. 16. PESTICIDES USED IN SOUTH AMERICANGMO-BASED AGRICULTURE: A REVIEW OFTHEIR EFFECTS ON HUMANS AND ANIMALMODELSSilvia L. López; Delia Aiassa; Stella Benítez-Leite; RafaelLajmanovich; Fernando Mañas; Gisela Poletta; NormaSánchez; María Fernanda Simoniello; and Andrés E.Carrasco.Advances in Molecular ToxicologyVol 6, 2012, (in press)
  17. 17. Legal actions to block effects of agrochemicalsSan Jorge, Santa Fe.Sentence: 800 m. for ground machine and 1500 m. aerial aspersion.Legal action. Santa Fe´s Court of Apppels.La Leonesa, Chaco.Sentence: 1000 m. for ground machine and 2000 m. aerial aspersion.Legal action. Chaco’s Superior Court .National Ombusman.Resolution recommending to the Minister of Agriculture to reviewclassification of all agrochemicals used in Argentina.
  18. 18. Glyphosate and teratogenesis
  20. 20. Laboratorio de Embriología Molecular Facultad de Medicina Universidad de Buenos Aires – CONICET   6th  European  Conference  of  GMO-­‐Free  Regions   Brussels  and  Ghent    16-­‐17  September,  2010    ARGE  Gentechnik-­‐frei,  Soy?  –GMO-­‐free  &  Sustainable     Vienna,  April  28  2011  
  21. 21. Two types of experiments were designed :1.  Embryos were cultured saline solution (BM) with 1/5000 dilution of GBH (430 uM)2.  200 to 300 pg of glyphosate (in 4.6nl) was injected in one blastomere of the two cell embryo (final concentration in the injected cell was 10 uM) 4.6nlInjection volume represent 1/220 fold thevolume of the injected egg (1ul) Izq Der
  22. 22. Both GBM and glyphosateinjection alter midline formationby down regulation of Shh andPax6In tadpoles down regulation ofOtx2 and Sox9 produces:1.  Microcephaly2.  Microphthalmia3.  Craniofacial disruption (branchial arches) .5.  Shortening of anterior posterior (AP) axis. Paganelli, et al 2010
  23. 23. In larvae stage both GBH and glyphosate produce disruption of development craniofacial due to inhibition of regulation of genes expressed in the embryonic midline (Shh, Otx2)1.  Microcephaly2.  Microftalmia3.  Craniofacial cartilages4.  Shortening of Anterior posterior axis.5.  Ciclopia and Holoprosencephaly Paganelli,  et  al  2010  
  24. 24. Retinoic acid (a derivate of vitaminA) plays an important role in theregulation of expression of genescontrolling early embryogenesis invertebrates.Retinoic acid is an importantmorphogen for the patternformation of three embryonic axis•  BH increase retinoic acid Gactivity.•  A antagonist (Ro) rescue the RGBH induced phenotype. Paganelli,  et  al,  2010  
  25. 25. In  conclusion   Synthesis  or  degradaNon     Glyphosate     (RALDH  or  cytochrome  P450     CYP  26  A,  B  y  C)   FGF  8     Anencephaly   Retinoic acid HOX    anterior-­‐posterior  axis   (HNF3B)   Cranial   Otx2     Shh   neural   Otocephaly   crest     HPE  and  cyclopia    
  26. 26. Retinoic acid
  27. 27. Retinoic Acid RA is a diffusible morphogen present in vertebrates that biding a family of nuclear receptors (RAR), regulating early genes during gastrulation (3 week of pregnancy) and late morphogenesis. RA regulates formation of AP embryonic axis In adults play role in fertility, vision, prevents neoplastic growth, and neurodegenerative disease. RA excess cause 20 % of the abortions and 35 % of the malformations during embryonic pattern formation
  28. 28. RA is ligand for a nuclear receptor and gene regulator
  29. 29. Retinoic Acid gradients in the embryonic A/P axis Pera et al 2009
  30. 30. Human syndromes caused by excess of RA (excess of vitamin A)
  31. 31. CRS: Caudal Regression Syndrome in mice.(excess of RA) (Padmanabhan R., Retinoic Acid-induced caudal regression syndrome in the mousefetus, Reproductive Toxicology, 1998)Exencephaly. Microcephaly, Microphthalmia. Exophthalmia.Holoprosencephaly,(HPE) Spina bífida y mielomenigoceleAgnatia or micrognatia, aglosia, palate agenesis, cleft palate craniofacialabnormalities. Astomia (mouth agenesis) and Anotia (auricular agenesis),Imperforate anus, Rectouretral fistula , Kidney malformations or kidneyagenesis, Criptoquidia. Gastroschisis,Reduction ribs numberNo tail and caudal vertebral defects,Limb malformations (meromelia, sirenomelia* (see picture) andsyndactily)Pathological morphogenesis of heart, lung, kidney, pancreas)
  32. 32. Caudal Regression Syndrome could be explained as: A disorder of embryonic midline formationresults in the inhibition of several regulatorypathways (Hox complex, A/P axis, Otx2, Shh, FGF8,etc.). Functional disruption of developmentalmechanisms: proliferation, apoptosis and cellmigration during early vertebrate morphogenesis.
  33. 33. Retinoic acid syndrome Inhibition of Otx2 (forebrain and midbrain) HPE (ciclopia and prosbosis) + agnatia and NEURAL CREST sinotia Inhibition of Shh (embryonic midline) HPE,NEURAL CREST situs inversus, limbs (amelia, sirenomelia, sindactily, etc.) Missregulation of Hox genes (affects A/P axis, vertebral identity and hindbrain) Malformations: lung, diafragm, eyes , hearth, digestive tract, kidney, gonades, etc.
  34. 34. Scientific reports associate chemicals and abnormalmorphogenesis for retinoic acid pathway disruption.Atrazine Lenkowski J, et al. Env Health Persp (2008, 2010)Tridimefon, Papis E, et al. Gene expression patterns(2007)Arsenic, Davey C, et al. Env Health Persp (2008)Alcohol, Kot-Leibovich H, et al. Dis Model Mech (2009)Azoles, Giavini E. and Menegola E., Tox. Letters (2010)
  35. 35. Glyphosate in mammalian embryos
  36. 36. Toxicokinetics of glyphosateDoses:IV 100 mg/KgOral 400 mg/kgSlowly disappearance from bloodIntravenous half life: 10 hr.Oral half life: 14 hr (degradation to AMPA 6%)Distribution (two compartment model) bothadministrations indicates that glyphosate penetrate easilyall tissues (according with Brewster et al 1991) Anadon, et al, Toxicology letter (2009)
  37. 37. Implantation in humans7 days 10 daysHuman Embryo 14 days 14 days
  38. 38. “These experimental conditions do not reflect human exposure, kinetics(absorption, distribution, excretion and their time course) in the mammalianorganism or factors such as the placenta barrier in the pregnant female. In nocase, exposure of the developing human fetus in utero would be similar to thatone of the frog or chicken embryos in the study by Paganelli et al.” (page 3-4) Bundesant fur Verbraucherschutz und Lebenmittelsicherheit 19 October 2010 Wrong!!!!!! Placenta is permeable to glyphosate. 15 a 20 % of glyphosate in blood, cross the placenta barrier.
  39. 39. In rats: In mammalians (rats). Teratogenesis at 3.5 g/kg (acute oral LD50: 5.6 g/kg) They used: 1 g/kg 075 g/kg 0.5 g/kg Administration 9 days/pc Gastrulation 7 days/pc Dallegrave et al, 2003LD50 5.6 g/kg glyphosate Roundup (Brasil) 38% glyphosate More information see:LD50 1g/kg POEA 18% POEA “Reply to the letter to the Editor Regarding our article” Chem. Res. in Toxicology, 24, 2011, 610-615
  40. 40. Commentstreatment was done after late gastrulation when theprimitive streak and the axis are already setup.craniofacial malformationsmalformation in the skeleton (vertebrae, ribs, limbs, femur,etc)All of these malformations are consistent with theincrease of RA during development.(see also “Reply to the letter to the Editor Regarding our article” Chem. Res. in Toxicology,24, 2011, 610-615)
  41. 41. Persistency of glyphosate in the soil
  42. 42. New evidences of Roundup (glyphosate formulation) impacton the periphyton community and the water quality offreshwater ecosystems. Marıa S. Vera, Leonardo Lagomarsino,Matıas Sylvester, Gonzalo L. Perez. Patricia Rodrıguez, Herna´nMugni, Rodrigo Sinistro, Marcela Ferraro, Carlos Bonetto, HoracioZagarese, Haydee PizarroEcotoxicology (2010) 19:710–721“Unexpectedly, we detected that a single application of glyphosate in2005 shifted the mesocosms from a ‘‘clear’’ to a ‘‘turbid’’ state whichremained until the next year. As was discussed above, the glyphosatemay be adsorbed to sediments and a slow later desorption mightproduce a long turn effect suppressing growth of the most sensitivegroups and favoring the abilities to compete of the more resistantalgae. This trend in long term effect was suggested by Holtby andBaillie (1989) who reported an enhancement of periphytic productionas a response to increased levels of phosphorus produced by a uniqueapplication of Roundup done 1 year before their experiment, carriedout in natural streams”
  44. 44. GENOTOXICITY (Comet assay ) Type A (normal) Type C Type E DNA Fragmentation Type B Type D Type F
  45. 45. Genotoxicity (comet assay) (Rio Cuarto, CORDOBA) Mañas y Aiassa 2010
  46. 46. PARAGUAY
  47. 47. PARAGUAY Benitez Leite 2010