Scientific Presentation: Sunday, Nov. 13, 11–12 p.m., Washington Convention Center
Mosaic aneuploidy, defined as coincidental chromosome losses and/or gains to deviate from the haploid chromosome complement, has been identified in both the developing and the adult mammalian central nervous system, including neural progenitor cells and functionally integrated mature neurons.
Aneuploidy arises through altered cellular mechanisms controlling growth, DNA synthesis and replication, and neurogenesis; during development, these processes are influenced by neurotransmitters and their associated signaling cascades.
Exposure to non-endogenous agonists such as amphetamines and nicotine can result in cell damage including oxidative stress or cleavage regulation problems and may contribute to DNA damage and misrepair through which aneuploidy can arise.
When used during pregnancy, drugs of abuse and alcohol can cross the placental barrier from the mother into the fetal brain, and are linked to developmental defects including abnormalities of cell proliferation, differentiation and death, loss of synaptic activity,
Sudden Infant Death Syndrome (SIDS), as well as pre- and postnatal growth retardation and Fetal Alcohol Disorders (FAD).
Here we show that in utero exposure to amphetamines or alcohol increases the incidence of aneuploidy in the developing brain.
Using metaphase spread analysis, embryos exposed at embryonic day 13.5 (E13.5) show a two-fold increase in total aneuploidy, from 23-25% in vehicle control versus 52% with d-amphetamine (10mg/kg) and 55-65% with ethanol (3-4.5mg/kg). For both drugs, hypoploidy (loss of chromosomes) was more prevalent than hyperploidy (chromosomal gains).
Metaphase spreads were also categorized by severity of aneuploidy: a mildly aneuploid spread has fewer than five chromosomes lost or gained; severe spreads have lost or gained more than five chromosomes.
Embryos exposed to d-amphetamine show a three-fold increase in the amount of mild aneuploidy compared to vehicle controls, while levels of severe aneuploidy remained consistent between treated and control embryos.
In contrast, embryos exposed to either 3mg/kg or 4.5mg/kg of ethanol display a three-fold increase in severe aneuploidy and less than twice as much mild aneuploidy.
These data identify alterations in neural aneuploidy as a new component in the etiology of disorders associated with prenatal exposure to alcohol and drugs of abuse.
Abstract 166.04 Summary and News Release
