마더리스크라운드

22. 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.

24. 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.

26. 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

28. 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)

29. Frances Kelsey

31. Impact of Maternal Health Conditions
 Diabetes
 Epilepsy
 Obesity
Symposium – Maternal Health in Pregnancy

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. Poster : Pregnancy outcomes in women reporting ingestion of levosulpiride
in early pregnancy

42. 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