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Diclectin in NVP, 44th 유럽기형학회보고 / 한정열 교수


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Diclectin in NVP, 44th 유럽기형학회보고 / 한정열 교수

  1. 1. President Award Lecture Making a difference – Concerned scientists in a contaminated world Susan Makris US. Environmental Protection Agency, National Center for Environmental Assessment, Washington Chemical pollution and environmental contamination : prevalent State of the environment and evidence of effects(know or suspected) on human reproduction and children’s health, serve as a constant reminder that our occupations offer us many opportunities to make a difference in the world.
  2. 2. We follow in the footsteps of many dedicated, intelligent, creative, hardworking, and ethical scientists who identified a problem, solved mystery, took a stand and/or instigated a change that had tremendous impact on the environment, the science and ultimately on human health. Their stories provided a source of inspiration and hope for the future.
  3. 3. Silent Spring was published on 27 September 1962 detrimental effects on the environment—particularly on birds— of the indiscriminate use of pesticides brought environmental concerns to the American public. Silent Spring was met with fierce opposition by chemical companies, but it spurred a reversal in national pesticide policy, led to a nationwide ban on DDT for agricultural uses inspired an environmental movement that led to the creation of the U.S. Environmental Protection Agency
  4. 4. Endocrine disrupting chemicals alter development of the fetus in the womb by interfering with the natural hormonal signals directing fetal growth. Their impacts, sometimes not detectable until years or decades after exposure, include reduced disease resistance, diminished fertility and compromised intelligence and behavior. Theodora Emily Colborn(née Decker; March 28, 1927 – December 14, 2014) was Founder and President Emeritus of The Endocrine Disruption Exchange (TEDX)
  5. 5. Frances Kelsey
  6. 6. Impact of Maternal Health Conditions  Diabetes  Epilepsy  Obesity Symposium – Maternal Health in Pregnancy
  7. 7. Diabetes in Pregnancy : Impact on fetal and childhood health PGDM : 0.5% and rising Associated : miscarriage, congenital defects, fetal death, macrosomia and cardiomyopathy Cardiomyopathy : poor diabetic control, increase of IUFD Later of life : increased risk of diabetes and cardiovascular disease Prevention : optimal glycemic control, planning pregnancy with HbA1C as near normal as possible
  8. 8. Epilepsy in pregnancy AEDs : increased malformation rate Valproate : poorer neurodevelopment, increased rate of autism dose dependent risk to the developing brain 예, 2000mg daily – can not live independently 200mg daily – went to college, work as an engineer CBZ, topiramate, phenytoin, phenobarbital and lamotrigine(high dose) : increased risk of malformation less clear on neurodevelopment Levetriacetam : not been associated with malformations and neurodevelopment
  9. 9. Obesity in Pregnancy: Strategies to prevent adverse outcome UK : obese – more than 20% of women Obesity in pregnancy : GDM, macrosomia, complications in labor and delivery UPBEAT(UK Pregnancy Birth Eating and Activity Trial) : RCT 1,555 women in early pregnancy Intervention : low glycemic Index diet 1:1 health trainer Handbook, DVD Result : Reduce gestational weight gain Not prevent GDM, But need strict GDM definition Suggestion : Stratification of women by risk of GDM early in pregnancy - most likely to benefit from early intervention Pre-pregnancy interventions
  10. 10. The Placenta An International network(PlaNet) to evaluate a human placental testing platform for chemicals safety testing in pregnancy Human placenta : a critical life-support system for rapidly growing fetus a unique species specific in structure and function Pressing challenge of providing better advice on the safety of prescription medicine and environmental exposure in pregnancy HPTs(Human placental test system) : pl. pharmacokinetics, dysregulated pl. function, influx/efflux transport polymorphism PlaNet : international consortium clinicians, physiologists, pharmacologists, bioengineers, mathematical modelers a roadmap to understand fundamental human placental transfer, toxicity mechanisms, and to progress HPTSs
  11. 11. Prenatal metal exposure and effects on the placenta: DNA methylation as a putative Mechanism of action Metals(arsenic and cadmium) : food and drinking water Metals : directly toxic to the pl. placental accumulation Prenatal cadmium and arsenic exposure : impaired fetal growth Epigenetic alteration and telomere length( a marker for biologic ageing) : potential mode of action Arsenic and cadmium : influence of global DNA methylation in human pl. Arsenic : longer placental telomeres The Placenta
  12. 12. The Placenta Preeclampsia : Free fetal hemoglobin as endogenous toxic compound, new etiological mechanism and potential target for treatment (Sweden) PE : 8.5 million women in the worldwide PE evolves by 2 stages : 1st: defect formation of placenta (oxidative stress- aggravates vascular function in pl. ) 2nd: clinical manifestations( hypertension and proteinuria after 20 GWs) In PE model : An important mechanism in pathophysiology of PE Free fetal hemoglobin(HbF): production, accumulation in pl. and maternal circulation(pl barrier damage) : 14 GWks HbF and metabolite : pro-inflammatory, pro-oxidative tissue damaging and vasoconstrictive properties A1M(alpha1-microglobulin) : synthesis at liver, anti-heme and anti-oxicative
  13. 13. PE women(previous study) : Increase A1M and HbF in urine (as a biomarker) Therapeutic effects of A1M on HbF induced tissue damage : shown in ex vivo placental perfusion experiments and tissue damage was reversed The Placenta
  14. 14. Reproductive toxicity testing in a regulatory context Reproductive toxicity : divide into effects on fertility and developmental toxicity Fertility : covers functional fertility, morphological and histological changes related to reproductive organ in male and female as well as the ability to produce offspring and to nurse them Developmental toxicity : any effect interfering with normal development of the organism, before or after birth and resulting from exposure of either parent prior to conception, or exposure of the developing organism during prenatal development, or postnatal development, to the time of sexual maturation ICH Guideline
  15. 15. Revision of the ICH guideline on detection of toxicity to reproduction for medical products For major revision of ICH S5 guideline(1993) : has an excellent safety record(better labeling and more cautious drug prescribing) : aim to further improve reproductive and developmental safety testing for new drugs Additions to the guideline : limit dose setting based on exposure, maternal toxicity, biopharmaceuticals, vaccines, testing strategies by indications(eq. cancer therapies), developmental immunotoxicity, male mediated developmental toxicity, human risk assessment( including exposure- based safety margins) Reducing animal test by using modern technology(eq, microsampling, fetal imaging, etc) Emerging issues : epigenetics, microbiome Outside of ICH regions: eq. China, India
  16. 16. Poster : Pregnancy outcomes in women reporting ingestion of levosulpiride in early pregnancy
  17. 17. Korean abstract  Assessment of neural toxicity for pharmacological compounds in hESCs EB Jeung  The effects of caffeine and bisphenol-A singularly or in combination on cultured mouse embryos SY Nam  Curcumin dose-dependently improves spermatogenic disorders induced by exogenous scrotal heat stress in mice MJ Yon  Lycopene inhibits nicotine-induced embryonic teratogenesis and vasculogenic disorders of yolk sac placenta through its antioxicdative, anti-apoptotic and anti-inflammatory activities SY Nam  Capsaicin inhibits spermatogenic cell death induced by scrotal hyperthermia via its anti- oxidative and anti-apoptotic activities SG Park  Combined repeated dose and reproductive/developmental toxicity screening test of cerium oxide nanoparticles in rat JS Lee