Student Research: Jing Chen

, Environmental Toxicology (Tox), 2010
Faculty Advisor: Lucio G. Costa

The Upregulation of Cholesterol Transporters and Cholesterol Acceptor-mediated Cholesterol Efflux in Brain Cells as a Novel Mechanism of Developmental Neurotoxicity: Ethanol and Retinoic Acid


Abstract

In utero alcohol exposure may cause fetal alcohol syndrome (FAS), a developmental disorder that is characterized by distinct facial features, growth retardation, and brain abnormalities. Studies showed that patients from FAS share profound similarities with those exposed prenatally to retinoic acid (RA), and those from Smith-Lemli-Optiz syndrome, a disease caused by genetic deficiency in cholesterol synthesizing enzymes, suggesting that these disorders may have a common mode of action. In this study, we investigated the effect of ethanol and retinoic acid on cholesterol transporters ATP-biding cassette family member A1 and G1 (ABCA1 and ABCG1) as well as ABCA1-induced lipoprotein formation in primary astrocytes and neurons as potential mechanisms involved in these conditions.

We found that retinoic acids, through up-regulations of cholesterol transporters ABCA1 and ABCG1, increased cholesterol efflux and decreased total cellular cholesterol in astrocytes, similar to that previously observed with ethanol. In addition, we found that ethanol and retinoic acid together had an additive effect in increasing cholesterol transporters and inducing cholesterol efflux from astrocytes. In neurons, however, we found that ethanol, although significantly increased ABCA1 and ABCG1, did not affect cholesterol efflux. In fact, our results suggest that ABCA1 and ABCG1 did not play a significant role in facilitating cholesterol efflux from neurons. Astrocytes are known to generate and release lipoproteins which are the major cholesterol carriers in the central nervous system. We found that ethanol increased the generation and altered the composition of astrocytes-generated lipoproteins, leading to an increase in astorcyte-related lipoprotein-mediated cholesterol efflux from both neurons and astrocytes. Protracted incubations of neurons in the presence of lipoproteins decreased neuronal cholesterol content and neuronal survival. In conclusion, we have found that ethanol and retinoic acid affect cholesterol homeostasis in astrocytes and neurons which is a mechanism involved in alcohol and RA-induced embryopathy.