Ethanol-Induced Neural Crest Apoptosis Is Coincident with Their Endogenous Death, But Is Mechanistically Distinct

Abstract

The ability of both acute and chronic ethanol exposures to elicit cell death within specific embryonic and adult tissues is believed to partly underlie ethanol's pathogenicity; however, the mechanism underlying this cell death is unknown. This study partially characterized the mechanism of ethanol-induced neural crest cell death in a chick embryo model of fetal alcohol syndrome. In situ DNA end-labeling demonstrated this cell death was apoptotic and occurred at embryonic ethanol levels as low as 42 mM. Regardless of the initial exposure time, this apoptosis always appeared at a distinct developmental time point simultaneous with the normal deletion of a cranial neural crest subset. This suggested that ethanol might act through aberrant activation of the endogenous death pathway; however, ethanol exposure failed to induce two components of this pathway, the homeotic transcription factor msx-2 and the growth factor bone morphogenetic protein 4. Both endogenous and ethanol-induced death were blocked by local application of an interleukin-1beta converting enzyme/CED-3 protease (caspase) inhibitor, showing that the two paths converge mechanistically and suggesting the potential to prevent this aspect of ethanol's teratogenicity. Ethanol exposure did not significantly alter cell proliferation within neural crest-populated regions, suggesting that susceptibility to ethanol-induced death did not involve exit from the cell cycle. Apoptotic deletion of cranial neural crest could partially explain the craniofacial deficits characteristic of the fetal alcohol syndrome.

Ethanol Consumption during Early Pregnancy Alters the Disposition of Tangentially Migrating GABAergic Interneurons in the Fetal Cortex

“…However, the same studies by Miller and colleagues reported an overall loss of cortical neurons postnatally. A recent report also indicated decreased number of GABAergic cells in the adult guinea pig and rat cortices (Moore et al, 1998;Bailey et al, 2004), an effect that could be attributed to ethanol inducing apoptosis (Bhave and Hoffman, 1997;Cartwright et al, 1998;Cheema et al, 2000;Dikranian et al, 2005). The discrepant results could be reconciled by hypothesizing cell death occurring in the immature cortex later than E14.5, including early postnatal ages, that is exacerbated by gestational ethanol.…”

Hindbrain and Cranial Nerve Dysmorphogenesis Result from Acute Maternal Ethanol Administration

“…Although these authors suggested that dysmorphology of the glossopharyngeal and vagus cranial nerves may be attributed to ethanol's effects on neural crest cells derived from r6 and r7, the pathogenesis for these anomalies was never experimentally confirmed. Work from our laboratory [Kotch and Sulik, 1992;Dunty et al, 2001] and others [Cartwright and Smith, 1995a, b;Cartwright et al, 1998] has shown that highly migratory cell populations, such as the neural crest, are very sensitive to ethanol exposure during embryogenesis. It is likely that abnormalities of the proximal sensory ganglia noted in both the current in vivo and previous in vitro study [Van Maele-Fabry et al, 1995] are a result of a direct insult to this precursor cell population.…”

Embryonic Cerebral Cortical Progenitors Are Resistant to Apoptosis, but Increase Expression of Suicide Receptor DISC‐Complex Genes and Suppress Autophagy Following Ethanol Exposure

“…Prenatal ethanol exposure during a crucial developmental period in the rat (gestational day [GD] 6 to birth) leads to a significant decrease in the number of neurons generated during the peak period of neurogenesis (Miller, 1988), and consequently, a decreased neuron number in the mature cortex (Miller and Potempa, 1990). This cell loss has largely been attributed to the ability of ethanol to induce apoptosis (Bhave and Hoffman, 1997;Cartwright et al, 1998;Bhave et al, 1999;Cheema et al, 1999;McAlhany et al, 2000;Ramachandran et al, 2003;Young et al, 2003;Takadera and Ohyashiki, 2004;Dikranian et al, 2005). Although we know that ethanol can induce apoptosis of fetal cortical neurons in late gestation (Ramachandran et al, 2003), relatively few studies (Kentroti and Vernadakis, 1991;Hao et al, 2003;Santillano et al, 2005) have focused on the apoptotic effects of ethanol on embryonic neural progenitors during early neurogenesis.…”