41차 유럽기형학회 보고

1. Korean Motherisk
한정열 MD,PhD

3. Education course : Testing stratiges for BioPharmaceuticals
E-1 : Introduction into BioPharmaceuticals and DART
M. Beekhuizen, Netherland
8. Sept
Aim : Overview of stepwise approach to follow on preclinical
DART testing for biopharmaceuticals

4. Definition biopharmaceuticals
Biotechnology-derived pharmaceuticals

8.  A scientific-based case-by-case approach is
considered the most appropriate for nonclinical
safety assessment of biopharmaceuticals.
 There is not one standard approach applicable
per biopharmaceutical subclass
 The stepwise approach is similar for general toxicity
as for DART, however DART specifics need to be
considered
Conclusions :

9. 8. Sept
Why test vaccines for developmental toxicity?
– possible specific risks to reproduction

17. 8. Sept
Goal :
To enhance the ability of course participants to approach NHP
DART study design and implementation in an effective, case-by-
case manner.

26. 9. Sept.
ETS presidents Award Lecture
: A Ornoy, Israel
Diabetic embryopathy: from clinical to molecular studies in
experimental animals and man – some historical perspectives
Before discovery of insulin : 1921
Severe fertility problem, Sp. Abortions, fetal death
Slight neurobehavioral development problems( mainly
inattention, slight gross and fine motor delay) : PGDM, GDM
hyperglycemia, embryonic malnutrition, oxidative stress
maternal diabetes induced change in embryonic gene expression
(heart, CNS, and gene related to oxidative stress and hypoxia)
Diabetic embryopathy and fettopathy etiologies : embryonic
metabolic/nutritional/endocrine disturbance/hypoxia/epigenetic
changes

27. Symphosium 1:
Developmental toxicity of nanoparticles-effects, issues and directions
for future research
S1-0 : Introduction: Light and Ultrastructural Morphology and
Permeability of placenta barrier
nanoparticles : one of most challenge research target in toxicology
nanoparticles : 1-100nm dimension
accumulate cellular organelles , damage to cellular cytoplasm
capacity to placental barrier , pass to embryonic/fetal tissue and organ
<100nm – go to cell by passing cellular membrane
<40nm – go to cellular nuclei
<35nm – go to brain by passing BBB
- so, brain is target
Placenta barrier : very strong like BBB
( coherent endothelium, basement membrane, surrounded by
syncythiotrophoblast cells with tight epitheliag junctions)
9. Sept.

28. S1-1: Prenatal exposure to nanoparticles effects and potential
mechanisms
Differ compared to that of bulk materials
Interfere with intrauterine development
Effects of gene expression, function of CNS system, immune
system, and male reproductive system.
Generate oxidative stress and inflammation
Interfere placental vasculization
Lung inflammation- mediators cross placenta –
interfere fetal development
For study - particle size, chemistry, surface area, route of
exposure
9. Sept.

29. S1-2: Nanoparticles and early human placenta – sophisticated
Matter meets Sophistigated Tissues
Pharmaceutical industry
Concern due to size
Identification of “nano-thalidomid before marketing
S1-3: Knocking at the door of the unborn child: issues in
developmental and placental nanotoxicology and direction
for the future research
a variety applications
Concern
- 18nm particle were transferred to embryos 24 hr after IV
Nanotoxicology 3 principles
1. nanomaterial uptake
2. surface effects
3. material properties
Basis for understanding of specific reaction & interactions
between nanoparticles and transplacental transfer
9. Sept.

30. 9. Sept.ETS/TS Exchange lecture : Myth or Merit : The
use of a second species in Developmental
Toxicity Testing
ETS subtitles : More safe drugs by less in vivo testing?
Issue & limitation are highlighted
Small molecule pharmaceuticals: tested in rats and rabbits for
toxicity of embryo in 1960 following thalidomide tragedy
Two species has sufficient power
False positive : discontinuation valuable drugs & limit full potential
use
So, Q?
New paradigm need
Evidence based holistic hazard identification & risk assessment
together with less traditional animal testing for more safe drug

31. 9. Sept.
TS subtitle : Screening environmental agents
1960 thalidomide disaster : rodent & non-rodent toxicity testing
Reliable information on developmental hazard and dose response
Not yet norm: genomic metabolomics/proteomic profilling/in vitro
predictive models(eq. whole embryo culture, embryonic stem
cells)/testing non-mammalian species (eq. Zebra fish)
More common approach : laboratory animal test ( rat and rabbit)
Q of Rat vs Rabbit – neither species is predictive of risk to human
More thoughtful, directed, chemical specific approach is needed

32. 9. Sept.
Symphosium 2:
Cross industry data survey of the value of rabbit developmental toxicity
data in the risk of assessment for pharmaceutics
--- used as the 2nd species of developmental toxicity
S2-1: ICH origins of the “2nd species” project UK
S2-2: Scientific background
S2-3: Emerging data
S2-4: Industry perspective
S2-5: Regulatory perspective

33. 10. Sept.
Symposium 3 : Reproductive toxicity –endocrine mechanisms
S3-1: Identification and assessment of endocrine disruptors in wildlife and
humans –scientific criteria for regulatory decision making in the EU
-- risk factor for human fertility
S3-2: Exposure to ED in humans: assessing biomarkers of effect
S3-3: The screening of everyday life chemicals for endocrine activity –
data interpretation and impact
S33-4: Species difference in susceptibility to inhibition of fetal testis
steroidogenesis

34. 10. Sept.
Symposium 3 : Reproductive toxicity –endocrine mechanisms
S3-1: Identification and assessment of endocrine disruptors in wildlife and
humans –scientific criteria for regulatory decision making in the EU
S3-2: Exposure to ED in humans: assessing biomarkers of effect
S3-3: The screening of everyday life chemicals for endocrine activity –
data interpretation and impact
S33-4: Species differece in susceptibility to inhibition of fetal testis
steroidogenesis

35. 10. Sept.
Symposium 4 : Reproductive toxicity- epigenetics
S4-1: System and genome wide adaptation of the epigenome
to gestational stress
 Hypothesis that system wide DNA methylation changes early
in life in response to social stress occur in both animal and humans.
 “Adaptive genomic” mechanism that prepares life-long genome
programming to the anticipated life long environment based on stress
signal received during gestation and early life.
 Glucocorticoids: act as “integrators” that translate the social stress
signals during gestation to genome wide methylation changes across
multiple systems

36. 10. Sept.
S4-2: Sex-specific transcriptional and epigenetic signatures associated
with peripheral leptin-resitance
 Non-communicable disease(NCDs) : 60% of worldwide deaths
 Next decade : 17% increase
 Fundamental misconception : Obesity, NCDs
 Paradime shift : DOHaD
 Early nutritional events: influence on later life health through
epigenetic process
 Evidence : maternal obesity and Type 2 diabetes at conception,
gestation & lactation promote development of obesity and
diabetes of offspring in their adulthood
 2 generation mice model : Obese and diabetic with CD during
periconceptional/ gestational/lactation period led to
sex specific shift form susceptibility to resistance to HFD in
female offspring only
 Sex specific liver disease risk : unsuspected role of Lepr gene in
peripheral sex specific leptin resistance

37. 10. Sept.
S4-3: Diabetic embryopathy : the role of epigenetics
 Epigenetic information : silencing or activation of genes
heritable change in gene expression
without changes in DNA sequence
 Hyperglycemia affects epigenome
 Oxidative stress/ apoptosis/hypoxia 에 반응하는 유전자의
epigenetic changes
eq. NRF2-mediated oxidative stress response pathway
Endoplasmic reticulum pathway
 Maternal diabetes seems to cause long lasting changes in
the embryonic epigenome by different mechanism.
These changes might be responsible to the diabetes induced
teratogenicity

38. 11. Sept.
Symposium 5 : Regulatory acceptance of alternative/in vitro methods
S5-1: Bottlenecks for the implementation of alternative methods in
regulatory reproductive and developmental toxicity testing
: Alternative method in regulatory method not easily accepted
whole embryo culture/zebrafish embryotoxicity/ embryonic stem cell
S5-2: Validation- an intrinsic part of safety assessment science
: reliability / relevance
S5-3: Science for or science based regulation: is there a missing link?
: Yes

40. Abstract
Characterization of phosphatidylethanol blood concentrations
for screening alcohol consumption in early pregnancy
Termination rate in Korean pregnant women who received counseling in
a teratology information service in the first trimester of pregnancy due
to exposure

41. Abstract
Effects of ß-carotene in cultured mouse embryos exposed to nicotine
Cunmei Lin, Sang-Yoon Nam Chung-buk natioanal University
Evaluation of human embryonic stem cell to screen developmental
Toxicants
EM Jung Chung-buk natioanal University

42. Diet and Autism spectrum disorders(ASD)
Yasmin H.
Departmenet of Human nutrition, The University of Alabama, USA
No clear etiology or cure for ASD
Nutritional factor may play a role in Tx of ASD
restriction of food allergens, probiotics, ketogenic diet, yeast free diet,
gluten and casein free diet
Methods: literature review ; 3 types of diet
casein free –gluten free diet(GFCF), ketogenic and antioxidant diet
Results:
GFCF diet show the most promise of efficacy
however, inconvenience and limitation
Conclusion : GFCF requires further safety studies.

43. Synergistic use of ex vivo and in vitro placenta model
systems to study various aspects of nanomaterial
behavior at the placental barrier
Tina BT.
NP(fluorescent polystyrene) is increasing production.
Major potential for the development of novel thearapeutic
strategies to treat specifically either the mother or the
developing fetus. So issue is for trans-placental transfer or
placental effects
NP 50, 80, 240, 500nm
Ex vivo human placental perfusion system
2 novel placenta system(for mechanistic study):
a perfused transwell co-culture system
a 3D placental microsphere model
240nm : taken by placenta
cross placental barrier without affecting the viability
of placental explant
Established systems for mechanistic study

44.  Biopharmaceuticals & DART
 Nanoparticles
 2nd species of developmental toxicity
 Endocrine disruptor
 Epigenetics
 Regulatory acceptance of alternative/in vitro methods
Summary