6. ETS education course
“Omics for beginners”
paramount importance in reproductive toxicology research
toxicogenomic and metabolomic data as well as bioinformatics is
expected to play an increasing role for reaching the ultimate goal
of chemical safety for man
Currently, there are 10,000 to 30,000 chemicals in world-wide commerce
in need of hazard data for assessing potential reproductive toxicity
health risks. The traditional animal study designs cannot accommodate
the evaluation of this large number of chemicals and bioinformatics
technologies are currently being developed to make the goal of chemical
safety for man reachable.
7.
8. I. Exploiting the Revolution: Mouse Genetic and Genomic Resources for Reproductive Health Research .
Dr. Lee B. Smith - MRC, Edinburgh U.K
16. IV. HTS and Computational Modeling for Developmental Toxicity
Dr. Thomas B. Knudsen - USEPA Research Triangle Park, NC, USA
17.
18. ETS symposium 1 - maternal and childhood asthma:
causes, consequences and treatment
Asthma, asthma medications and their effects on maternal/fetal outcome
during pregnancy
Rocklin RE
Asthma: Chronic inflammatory disease of lower airway
Bronchial obstruction
Symptom: wheezing, shortness of breath, chest tightness, cough
Inflammation: 특이 싸이토카인( IL-4, IL-5, IL-13)을 내는
Type 2 helper T cells에 의해서 가속됨.
이들 싸이토카인이 airway에 염증세포들(eosinophils,
neutrophils 등)을 chronic infiltration시킴
Prevalence : 4-8% in USA
19. Effect of pregnancy on maternal asthma
Increased estrogen
Increased pregesterone
B2-adrenoreceptor hypo-responsiveness
Female fetus
Altered immune function
1/3 악화 1/3 변화 없음 1/3 호전
20. Effects of maternal asthma on pregnancy and perinatal outcomes
Lung inflammation
Maternal hypoxia
Altered placental function
Fetal gender
Asthma exacerbations
Low birth weight Preterm labor Preeclampsia C/S
21. Reproductive issues in the development of asthma medications
Tx goal: maintain control of asthma for maternal health and
quality of life as well as normal fetal maturation
I. Inflammation control : inhaled corticosteroid,
leukotrien inhibitors,
chromones
II. Relieve sx : B2-agonist
theophylline
22. Anti asthma medications의 development에 고려점
I. Toxic considerations : adverse fetal outcome
Route of administration
Metabolism
Dose
Whether the agent crosses the placenta at the point of development
at the time of exposure
Pharmacologic activity
Non-target mediated effects
Binding affinity to target in relation to inactive or active forms of the
receptors
Toxicokinetics
II. VLA4 antagonism as a specific example of issues related to asthma
drug development
23. Risk evaluation associated with asthma medication use during pregnancy
1. General considerations : Risk and benefit of asthma medication
2. Human data :
RCT, generally not feasible
Case-control study, Cohort study
Do not by themselves prove causality
Often limited by inadequate sample size
3. Animal data :
Animal developmental toxicology experiments
Designed to maximize the potential toxic effects by using large dose
Negative result: a low potential for human development toxicity
Positive result: less predictive for human toxicity
(species difference, clinically irrelevant high dose, maternal toxicity?)
24. Drug label categories and step therapy recommendations
단점: paucity of adequate and well controlled data in human
Over reliance on animal data
Clinical interpretation of C is very difficult
Route of administration와 임싞중일어나는 약물의 약동학과
약력학을 고려하지 않음
Inhaled corticosteroid(budesonide) : B
25. ACAAI-ACOG recommendations for pharmacological step
for chronic asthma during pregnancy
- 임싞 시 사용될 수 있는 약: inhaled corticosteroids, theophylline,
cromolyn, long acting b2 agonist, leukotriene antagonist(monterukast,
zafirlukast)
- Oral steroid: maintain on lowest effective daily dose of steroid
27. Maternal and childhood asthma: Risk factors, interactions,
and ramifications
Dietert RR
Fetal and early neonatal development: critical period
“Barker Hypotheisis”: Prenatal environmental determination
of Later life diseas
Recent examples of early life environmental determinations
1. Developmental Pb on specific childhood neurobehavior outcomes
2. Fetal alcohol on CNS
3. Developmental PCBs(polycyclic chlorinated biphenys) on adult
pregnancy
4. Arsenic and resistance to infectious disease
5. Prenatal stress on the HPA axis
6. Undernutrition and cardiovascular diseas
7. Pesticides and neurodegenerative conditions
8. Developmental estrogens and risk of prostate cancer
9. Developmental high fat intake and liver disease
10. Low vitamin D level and GI tr allergy
28. Maternal and childhood asthma - Risk factors
Maternal asthma: potential implications
A family history of atopy and asthma: inheritance of allelles driving
Th3-bias and skewed inflammatory responses
not pure due to 1. epigenetic alterations-several generations
2. environmental risk factors-differential effects
Asthma management in pregnancy : err
Th-2 biased environment : exacerbate sx of Th2-associated disease
29. Immune dysfunction based-disease and childhood
¼ of children : immune dysfunction based conditions(asthma,
autoimmune ds, inflammatory conditions)
Childhood asthma : 선진국에서 최근 크게 증가
Childhood asthma : 25.9%
30. Risk factors for the child
“largely developmental disease” : its origin in early life
Genetic factors- alleleic and epigenetic
alleric varients of gene encoding cytokines, cytokine receptors 등
in animal model, specific genotypes: predispose for Th2-biased
adaptive immune responses & hyperinflammatory response in
tissue
genes involved : related to immune, inflammatory signaling
and/or functional response
examples: minor allelle of Nrf2, common allele for IL-13
IL-1 receptor like 1 polymorphisms, NOD1 and NOD2
alleles for both TLR-2 and TLR-4 – traffic related air pollutants
Interactions between genetic and environmental factors:
maternal and child polymorphism for antioxidant status vs prenatal
paracetamol(acetaminophen) – affected risk for asthma
Study of epigenetics and potential transgenerational effects : infancy
32. Safety testing gap for childhood asthma
Asthma : most common chronic condition of children
greatest number of school absence for chronic disease
입원 치료의 3번째 원인
Annual cost : 18 billion dollars
Immunotoxicity safety testing for childhood allergy and asthma:
Not routine for most drugs and chemicals
“Safety testing gap”
Outcome of the gap: most children must be treated for childhood
asthma rather than benefiting from an aggressive safety
testing program to prevent childhood asthma
one solution: same level of attention for drug development
33. Endpoints to monitor the management of childhood allergy and
asthma : 천식의 위험을 스크린 하는데 유용
levels of IgE antibody, T2 cytokines, eosinophils in bronchial lavage,
production of inflammatory mediators, chemokine in the airways,
alterations in pattern recognition receptors, changes in bronchial reactivitiy
and architectiure
스크린이 효율적이기 위해서
1. age-relevant immunotoxicity safety screening be widely
employed in evaluating the safety of drugs and chemicals.
2. Immune respiratory challenge (eq. respiratory viral infection)
포함되어야 함.
34. Consequence for children diagnosed with asthma
Childhood asthma: a significant lifelong health burden
beginning in children and entryway to potential additional
chronic disease
Child with asthma is a high risk group for later childhood and
adult onset conditions: allergic rhinitis, atopic dermatitis, otitis
media, increased respiratory infections, behavioral disorders, obesity,
olfactory disorders, and lung cancer
The elevated risks be connected to fundamental
immune dysfunction associated with childhood asthma:
Th2 biased responses, improper innate immune
maturation, improperly regulated inflammation in the
airways, other tissues than can affect metabolism and risk
of lung cancer, cytokine imbalances that can affect sleelp
patterns, moods and sensory functions
35. ETS symposium 2 – Prenatal and postnatal causes for obesity
and their complications later in life
Asher Ornoy
PGDM & GDM : Sp abortion, IUFD, congenital anomalies,
neurodevelopmental problems, increased risk of
perinatal complications
또핚, fetal growth disturbance: increased or decreased BW.
36. Optimal control of maternal blood glucose: reduce these changes
Metabolic syndrome: hypertension, cardiovascular complications,
type 2 diabetes
Excessive maternal overweight and obesity or excessive wt gain:
Increased obesity and complications in the offspring.
FGR and Macrosomia : “metabolic syndrome”
37. Mechanisms underlying these long term effects on growth:
Insulin resistance, fetal hyperleptinemia,
hypothalamic changes, probably epigenetic changes
Prevention of metabolc syndrome:
Tight dietary control and physical activity in the children born to
obese or diabetic mothers
38. Long-term effects of FGR and of Macrosomia- the metabolic syndrome
Reaven(1988) :
Insulin resistance and secondary hyperinsulinemia –
etioology of diabetes type 2, cardiovascular disease, hypertension
- 3 components of main complications of FGR and macrosomia at
adulthood
- then called “ syndrome X, later modified to the “metabolic
syndrome”
- glucose intolerance,
increased insulin secretion, increased blood triglyceride, decreased
HDL, hypercholesterolemia, cardiovascular disease, diabetes type 2
39. Thrifty phenotype hypothesis:
- epidemiological association between poor fetal growth, type 2
diabetes, metabolic syndrome result from the effects of poor
nutrition in early life, which produces permanent changes in
glucose insulin metabolism
reduced capacity for insulin secretion and insulin resistance
obesity, aging and physical inactivity : cardiovascular and metabolic
complications
the result of adaptational change of the fetal endocrine-metabolic
mechanism to the impaired intrauterine milieu to assure survival in
the short term
40. FGR이 일어났던 time과 정도에 따라, 각 개인들에서
metabolic syndrome의 parameter가 다르게 나타남 :
Symmetric type of FGR : arterial hypertension later in life
Asymmetric type of FGR : glucose intolerance and type 2
diabetes.
GDM and Obesity associated macrosomia : strong predictor
of metabolic syndrome
41. Mechanisms of long term outcome of children born SGA or
macrosomic
1) The “Thrifty” genes or “Barker” hypothesis(metabolic syndrome)
2) Insulin resistance
3) Changes in leptin secretion and leptin insensitivity
4) Hypothalamic programming
5) Epigenetic changes
42. 1) The “Thrifty” genes or “Barker” hypothesis(metabolic syndrome)
-“thrifty phenotype” hypothesis : Hales and Barker 1992
407 men Hertfordshire, England 1920-1930
226 men and women Preston, England 1935-1943
Size at birth and 1year of age
Prevalence of “thrifty syndrome” fell progressively in both men
and women with the increase in birth weight
At birth, subjects with the thrifty syndrome : small head
circumference, at 1year low weight and below-average dental
eruption.
Type 2 diabetes and hypertension : common origin in sub-
optimal growth and development in in utero
43. 2. Insulin resistance
Insulin resistance : fundamental and most important underlying problem in
the pathogenesis of the “metabolic syndrome”
Insulin resistance cause insulin over-secretion followed by insulin deficiency,
which is the basic pathogenesis of obesity and type 2 diabetes
In pregnant women with GDM, maternal hyperglycemia(diabetes) induces fetal
hyperinsulinemia.
Elevated fetal insulin affect its hypothalamic development.
Insulin in the brain decrease food intake, while insulin depletion(or resitance)
may promote hyperphagia.
Fetal intra-cerebral injection of insulin : decline of the NPY(Neuropeptide Y)
protein, NPY increase food intake.
These effects on the fetal brain : long lasting, affecting hypothalamic
organization and metabolism.
Increased insulin levels increase leptin secretion by adipocytes, further
decreasing food intake.
44. 3) Changes in leptin secretion and leptin insensitivity
Leptin : hormone secreted by the adipose tissue which acts as a sensor of
body fats.
Secteted in levels that directly correlate with body fat stores
Acts as an anorexogenic hormone in the brain
Controlling feeding behavior by specifically decreeing appetite
Leptin or leptin receptor animal or man : early onset obesity
Main action : in the hypothalamus
hypothalamus arcuate nucleus’ neuron : express several
peptides related to feeding behavior
45. “leptin resistance” : situation where leptin is elevated in the blood of
obese individual
occur in many obese people where food intake is
not reduce in spite of the increased leptin levels
different explanation: impaired transport through the BBB,
impairment of leptin signaling by the chronic high level of leptin
Placenta produces a significant amount of leptin
Insulin treatment increase the production of leptin by the placenta, as a
fetal cerculating leptin
Fetal hyperleptinemia(by maternal obesity or maternal increased wt
gain) : significnat influence on the fetal hypothalamus and on future
energy homeostasis
Mice lacking leptin : increased appatite, obese and become diabetic
due to development of insulin resistance
46. 4) Hypothalamic programming : the role of fetal nutritional imbalance
Hypothalamus : regulate food intake and energy balance
Different area for the regulation :
ventromedial hypothalamic nucleus : satiety
lateral hypothalamic area : feeding center
In these area, neurotransmitters(norepinephrine, serotonin,
GABA ext) are secreted.
이들 neurotransmitter의 metabolism의 변화는 food intake에 영향
Most important area : arcuate nucleus- have both central and
peripheral connections also containing leptin sensitive neuron.
NYP : a 36 amino acid peptide
released from the nerve terminals of the arcuate nucleus
and in other part of cerebral cortex.
involve in vasomotor reactivity, sexual function, promote
feeding and obesity
47. POMC(proopiomelanocortin derived peptides) :
inhibit feeding
glycoprotein which serves as multihormonal precursor
of corticotropin, lipotropins, melanotropins, dendorphins
The neurons secreting NPY of POMC have synapses with neurons located
in other parts of the hypothalamus associated food regulations, also with
neurons in the cerebral cortex, thalamus and brain stem.
Receive information from the periphery mainly through leptin and insulin.
Nutritional change of developing fetus( resulting in FGR or macrosmoia)
will induce long lasting changes in the hypothalamic centers that control
food intake.
Most hypothalamic connections in the human fetus seem to develop
during the second half of pregnancy
Hypothalamic disturbances may cause obesity and diabetes
48. 5) Epigenetic changes
How do intrauterine growth disturbances remain as a stable
memory in the later biology and behavior of the offspring?
New understanding of genome-function is emerging.
Genome-functionality is determined by DNA sequence, the
timing and expression of the genes.
Epigenome: molecular mechanisms that govern gene
expression in a time- and cell-type dependant fashion.
Early environmental exposures such as high glucose or
maternal obesity and overfeeding during pregnancy alter the
programming of genes by epigenetic markings, resulting in a
long term imprint on gene expression that lasts into adulthood.
49. Severe reprogramming of critical genes for development may result in
teratogenicity or early neurodevelopmental deficit,
Whereas responses in the physiological range would increase the risk of
development of neurobehavioral problems, obesity and thye 2 diabetes
later in life.
Homeobox PdX1 undergoes progressive epigenetic silencing in beta cells
in rodents that were exposed to intrauterine growth retardation and are
prone to develop diabetes.
Streptozocin induced type 1 diabetes in the rat results in genral DNA
hypomethylation in the liver.
Gluckman and Hanson: fetal undernutrition causes epigenetic changes that
can later in life, when nutrition is adequate or high, cause metabolic
imbalance resulting in the typical “metabolic syndrome”
Stevens : maternal undernutrition may induce epigenetic changes in the
offspring, especially in the hypothalamic neuropeptide(NPY, POMC) genes
that regulate energy balance.
One of the most important tasks of preventive medicine in the 21st century
50. ETS-T Debate- “All Mixed up about Mixtures:
How Big of a problem and What to Do about it”
Teratology society : low level of mixtures is OK
European teratology society :
sensitive endpoints of antiandrogen
1. anogenital distance
2. nipple retention
3. malformation : hyposphadia
0% + 0% + 0% = ~60%
“Paracelsus” : dose make poison
so, cumulative dose make risk.
51. Elsevier Award lecture :
Fetal malformations and early embryonic gene expression
response in Cynomolgus monkeys maternally exposed to
thalidomide
Makoto Ema
52. ETS Award lecture
“The Male conundrum”
John Tesh
Conundrum : confusion
BC 600, 피타고라스 : male essence for offsprings
아리스토텔레스 : Theory of epigenesis
Soul guide gradual epigenetic development
- - -
1993, Male mediated developmental toxicity
Male Female
Offsprings
53. Free Communications
In utero exposure to antiepileptic drugs: Cognitive development
and functioning of the child
University of Manchester, UK
Epilepsy : 198 Control 210
Sodium valproate (n=51)
: lower global cognitive ability, memory, attention, rate of learning,
language score
Dose dependent relationship was found, above 800mg/d increased
cognitive impairment.
Neurodevelopmental disorders of valproate vs control : OR 7.28
No significant association with lower cognitive or neurodevelopmental
disorders was founded born to women with untreated epilepsy(n=25) ,
carbamazepine(n=50), lamotrigine(n=29)
