Exposure During Development Flashcards
How many children have some developmental disability? Severe ones?
Autism?
17%
2%
7-12/1000 children are on autism spectrum
What is concept of environmental justice?
Do not occur in a vacuum.
Communities that are entrapped (poverty)
Genetic predisposition and social circumstances.
Access to medical care lacking.
Access to healthy diets
What are poor diets deficient in?
Calories Protein Iron Iodine Folates(vitb9) and vitB12
Sea salt does not have iodine!
Folate is most important (methylating agents to make nucleic acids)
What does methotrexate do?
Knocks out folate.
But fetus needs folate!
Mothers should be exposed to folate now! Takes time for it to build up in your system.
What are the principals of teratology?
• Suscep6bility depends on genotype of conceptus.
• Suscep6bility depends on developmental stage at exposure
• Malforma6on is caused by specific pathogenic mechanisms
• Rela6ve teratogenicity is influenced by maternal factors
• Abnormali6es by developmental stages:
– Func6onal deficit
– Growth retarda6ons
– Malforma6ons
– Adult disease may develop long aYer fetal exposure
• Developmental defects increase with frequency & degree as a func6on of fetal
dose
What is DES?
Diethylstilbestrol
Did not show vaginal lesions in f1 offspring.
Can animal studies predict congenital rubella syndrome?
No
Did animal studies predict thalidomide toxicity?
Some but not all. Big thing here is that animal studies cannot predict everything.
Tests never done for reproductive effects afterwards saw the phocomelia.
What are TORCH infections?
T-Toxoplasmosis O-Other (Zika, chicken pox, varicella, syphyllis, parvovirus) R-Rubella C=Cytomegalovirus H=Herpes
Mild maternal morbidity, but with serious fetal consequences.
Treatment of maternal infection does not have a corresponding impact on fetal outcome
MICROCEPHALY and metal retardation are big ones.
What is critical window for Rubella/Zika in fetal development?
3-16 weeks.
What is Rubella (German Measles/Congenital rubella syndrome?)
Patho: Togovirus
Mild flu like sympotoms
Incubation period = 2-3 weeks.
1st trimester: 50-95% cases
2nd: 25% cases
3rd:
When was rubella vaccine developed?
1970
What are critical days for ear and eye development?
Upper limbs?
Lower limbs?
Ears/Eyes: Days20-25
Upper limbs: 26-30th
Lower limb:31-36th
Twins show remarkable differences in response. (Both monozygotic and dizygotic twins)
What is classic triad of Congenital Rubella syndrome (CRS)?
Other manifestations?
Classic Triad
- Sensorineural deafness: 60%
- Congenital heart diz: 50%
- Ocular abnormalities: 45%
- ->1. Cataracts
2. Microophthalmia
3. Retinopathies.
Mental retardation LBW Thrombocytopenia purpura Hepaomegaly Facial deformities Microcephaly
Is MMR vaccine indicated in pregnancy?
NO. Live vaccine!
What is Zika virus?
Flavivirus spread primarily by A.aegypti + albopictus.
58 countries and territories have active Zika.
Adults are asymptomatic/mild.
> 30,000 cases in Brazil.
What is congenital Zika syndrome?
Fetal Death Still birth Neonatal death Developmental impairment ->motor/visual/microcephaly/cognitive impairment
Thinning of normal cortex. Occurs between 16-20weeks.
Folate (VitB9) Deficiency? Pathogenesis?
Folate needed for DNA syn (methyl-transferase) and b12 deficiency
Wont have any methylated DNA adducts.
Neural tube defects: spina bifida, large RBCs,
How does folate deficiency occur?
Metabolic dysfunction in mother.
Diet.
(Lack animal protein and green veggies)
Maternal smoking, alcohol, and kidney dialysis
->inhibit interactions
What are some drugs that interact with B9 receptor?
- Anticonvulsants (dec. levels)
- Metformin (dec. levels)
- MTX - Chemotx
- Sulfasalazine (chrons/UC)
What are s/sx of folic acid deficiency?
Neural tube closed at end of 1 month.
Defects range from anencephaly (lack of brain) to spina bifida.
Supplement with Folic acid 400mg QD
What is most common cause of preventable mental retardation in US?
Fetal alcohol syndrome (Pintar)
What are clinical features?
Decreased growth rate.
Facial abnormalities
Microcephaly
Microophthalmia
Hyperactivity
Delayed motor skills
Delayed language and learning
4-5drinks/day
Recommend zero alcohol!
What is thalidomide toxicity?
Neuropathy-adult
Gi stasis-adults
Dizziness and disorientation-adult
Teratogenesis: -Phocomelia Amelia Syndactyly Ear/eye defects.
What is MOA of pathogenesis of Thalidomide?
- Direct toxicity of affected tissues
- Arrested development of neural tissues
- altered permeability of blood vessels
- arrested development of critical blood vessels ***
Now being used as multiple myeloma, leprosy, difficult dermatological case
What was DEs first defined as?
1st non-steroidal estrogen
Clinical use for threatened miscarriage.
Mothers would develop clear-cell adenocarcinoma of the vagina.
Learned that placenta is not a complete barrier.
When does IUGR occur?
Weeks 16-38 of development.
Placental abnormaliOes • Pre-eclampsia or Diabetes • Chromosomal syndromes • Smoking • Alcohol • XenobioOcs (chemicals, drugs) • TORCH infecOons • Maternal undernutriOon
Dutch famine hypothesis:
Famine in 3rd trimester: glucose intolerance issues
1st trimester exposure: no such effect.
Big point is that babies are born that are “small for gestational age”
What are Barker studies?
Women give birth at early age-> obese quicker.
HYpertension
CV diz
Glucose intolerance
Dyslipidemias
Women who are heavy smokers look like this too.
What are endocrine disruptors?
DES was 1st.
Interfere with normal hormones functions.
Endocrine disruption is important, but controversy over which ones are significant.
What are main environmental chemical that we see?
Mercury
Polychlorinated biphenyls (PCBs_
Lead
Organophosphate pesticides (OP)
Why is mercury so useful?
Toxic to all organisms -antiseptic Biocide on plants and on crops As an antimicrobial preservative in vaccines Diuretic to poison
Where do we see methylmercury poisoning?
People who eat fish high on the food chain (shark/sword/tuna) multiple times a week.
Methylmercury poisoning from dumping into ocean.
Seychelle island- have complimentary diet of fruits and veggies.
Why are fish beneficial to nervous development?
Omega 3 for nervous system development
Protein quality
1 fish meal/week
Salmon low in mercury and high in omega-3s
Canned tuna is fairly high in mercury.
White tuna has much higher levels of mercury.
Where are there fish high in PCB?
Great lakes.
Decrease in cognitive function.
10% decrease in gestation growth.
What is current blood lead standard to prompt public health action?
> = 5ug/dL
NO SAFE LEVEL
IQ deficits
Translated to at least 3 pt drop in IQ
What is mechanism of OP pesticides?
Inhibit ACHe, ACH builds up at neuronal junctions
What kind of studies do FDA use do determine exposure to pesticides?
Animal studies based on “no observable dverse effect level”
Applies 3 10fold uncertainties
Really not based on anything
OP short half life. Cant get chronic picture unless you have multiple blood draws.
What did Columbia cohort show us about OP exposure?
CHAMACOS/Mt.Sinai
HIghest exposure of OPs -> lowest birth weight
Maternal urine associated with abnormal reflexes and decreased Bayley mental development scores at 24 months.
Pregnancy exposure is prob most important
7 IQ points lower!
FIFRA->advisory panel.
