Risks associated with prenatal exposure to alcohol Diane Black, Ph.D. Chair, EUFASD Alliance Adoptive mother to 3 young adults with FASD

Fetal Alcohol Syndrome FAS is diagnosed if the mother drank during pregnancy and the child exhibits the following: Retarded growth Characteristic facial features Neurological damage Lemoine (Ouest Medical,1968); Jones, Smith, Ulleland, Streissguth (Lancet, 1973) Fetal Alcohol Spectrum Disorder FASD covers the whole range of degrees and types of damage

Diagnosis using the 4-digit code Used with permission. Copyright Susan Astley

Mental illness >90% Early school leavers 60% Trouble with the law 60% Institutionalization (psychiatric, drugs- or alcohol addiction treatment, prison) 50% Inappropriate sexual behavior 50% Alcohol or drug addiction 30% Dependent living 80% of those over age 21 Streissguth et al. (CDC, 1996) Long term outcome FAS

“One or two drinks a week is not dangerous / will make the child more intelligent / does not affect development” You may have heard... Not randomized controlled trials Self-chosen groups Limited number of measures – what about risk of childhood leukemia? Slow bone growth? Risk of early addiction to alcohol? Higher reasoning skills? Etc.?

"We found that a rise in blood ethanol to a level in the range of 50 mg/dl for a duration of 30 to 45 min was sufficient to trigger a significant neuroapoptosis response deleting approximately 20,000 neurons per infant mouse brain." Young & Olney (Neurobio Dis, 2006)

“A safe level has not yet been established” You may have heard... This statement suggests that there is a safe level What do we mean by “safe”? If we mean “the child is clinically more or less like other children?” then we have some flexibility If we mean “providing an environment which will allow maximum development” then we cannot accept any risk Teratology: find No Observed Adverse Effect Level in animals, then give a x safety margin to extrapolate to humans

“Science has not yet understood how alcohol causes brain damage” You may have heard... Yes, but that is only because there are so many mechanisms that we probably haven’t identified them all yet! 1. Disrupted cellular energetics: altered glucose utilization and transport, suppression of protein and DNA synthesis, oxidative stress. 2. Impaired cell acquisition/dysregulated developmental timing: altered cell cycle; impaired neurogenesis and gliogenesis; mistimed events of cell generation, migration, neurite outgrowth, synaptogenesis, and myelination. more >>

1. Disrupted cellular energetics: altered glucose utilization and transport (49–53), suppression of protein and DNA synthesis (54), oxidative stress (see Number 6, below) 2. Impaired cell acquisition/dysregulated developmental timing: altered cell cycle; impaired neurogenesis and gliogenesis; mistimed events of cell generation, migration, neurite outgrowth, synaptogenesis, and myelination (55–63) 3. Altered regulation of gene expression: reduced retinoic acid signaling, effects on other transcription factors (64, 65) 4. Disrupted cell-cell interactions: inhibition of L1 cell adhesion molecule (L1 CAM) function (66–70) 5. Interference with growth-factor signaling or other cell-signaling pathways (71–77) 6. Cell damage/cell death: apoptosis (38, 72, 78–85), oxidative stress (79, 86–90), withdrawal-induced glutamatergic excitotoxicity (91, 92) 7. ‘‘Secondary’’ sources of damage: altered placental function or other intrauterine factors (93, 94), hypoxia/ ischemia (95–97), acetaldehyde formation (98– 3. Altered regulation of gene expression: reduced retinoic acid signaling, effects on other transcription factors 4. Disrupted cell-cell interactions: inhibition of L1 cell adhesion molecule (L1 CAM) function 5. Interference with growth-factor signaling or other cell-signaling pathways 6. Cell damage/cell death: apoptosis, oxidative stress, withdrawal-induced glutamatergic excitotoxicity 7. ‘‘Secondary’’ sources of damage: altered placental function or other intrauterine factors, hypoxia/ischemia, acetaldehyde formation Reviewed in Goodlett et al. (Society for Experimental Biology and Medicine, 2005)

Zero alcohol = zero risk Thank you