President Award Lecture

Making a difference – Concerned scientists in a contami-nated world Susan Makris US. Environmental Protection Agency, National Center for Environmental Assessment, Wash-ington

Chemical pollution and environmental contamination : prevalent

State of the environment and evidence of effects(know or sus-pected) on human reproduction and children’s health, serve as a constant reminder that our occupations offer us many opportu-nities to make a difference in the world.

We follow in the footsteps of many dedi-cated, intelligent, creative, hardworking, and ethical scientists who identified a problem, solved mystery, took a stand and/or insti-gated a change that had tremendous impact on the environment, the science and ulti-mately on human health. Their stories pro-vided a source of inspiration and hope for the future.

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

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 ex-

posure,

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)

Frances Kelsey

Impact of Maternal Health Condi-tions

Diabetes

Epilepsy

Obesity

Symposium – Maternal Health in Preg-nancy

Diabetes in Pregnancy : Impact on fetal and childhood health

PGDM : 0.5% and rising

Associated : miscarriage, congenital defects, fetal death, macro-somia and cardiomyopathy

Cardiomyopathy : poor diabetic control, increase of IUFD

Later of life : increased risk of diabetes and cardiovascular dis-ease

Prevention : optimal glycemic control, planning pregnancy with HbA1C as near normal as possible

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 neurode-velopment

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

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 poly-morphism

PlaNet : international consortium clinicians, physiologists, pharmacologists, bioengineers, mathematical modelers

a roadmap to understand fundamental human placental transfer, toxicity mechanisms, and to progress HPTSs

Prenatal metal exposure and effects on the pla-centa: 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

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 GWksHbF and metabolite : pro-inflammatory, pro-oxidative tissue damaging and vasoconstric-tive properties

A1M(alpha1-microglobulin) : synthesis at liver, anti-heme and anti-oxicative

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

Reproductive toxicity testing in a regulatory context

Reproductive toxicity : divide into effects on fertility and developmen-tal toxicity

Fertility : covers functional fertility, morphological and histological changes re-lated 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

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 prescrib-ing) : aim to further improve reproductive and developmental safety testing for new drugs

Additions to the guideline : limit dose setting based on exposure, maternal toxic-ity, biopharmaceuticals, vaccines, testing strategies by indications(eq. cancer therapies), developmental immunotoxicity, male mediated developmental toxic-ity, human risk assessment( including exposure- based safety margins)

Reducing animal test by using modern technology(eq, microsampling, fetal imag-ing, etc)

Emerging issues : epigenetics, microbiome

Outside of ICH regions: eq. China, India

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

Korean abstract

Assessment of neural toxicity for pharmacological compounds in hESCs EB Je-ung

The effects of caffeine and bisphenol-A singularly or in combination on cul-tured 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