Disruption of cholesterol homeostasis in developmental neurotoxicity

Marina Guizzetti, Lucio G. Costa

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Scopus citations

Abstract

Cholesterol (a major component of brain membranes as well as of membrane microdomains called lipid rafts that are involved in the transduction of morphogenic signaling pathways) plays a pivotal role in fetal development and, in particular, brain development. Cholesterol levels in the brain are regulated through its biosynthesis and through its trafficking and elimination. Genetic syndromes caused by mutations in enzymes in the cholesterol biosynthesis pathways leading to reduced levels of cholesterol cause severe neurodevelopmental abnormalities, underscoring the importance of cholesterol during brain development. Additional neurodevelopmental disorders have been recently associated with altered cholesterol homeostasis in the developing brain. Two developmental neurotoxicants, ethanol and retinoic acid, produce effects similar to the ones caused by genetic defects in cholesterol biosynthesis. These two teratogens affect cholesterol homeostasis by upregulating the levels of ATP-binding cassette cholesterol transporters and increasing cholesterol efflux and lipoprotein release in glial cells; lipoproteins in turn act as cholesterol acceptors and extract cholesterol from neurons, leading to reduced levels of cholesterol and increased cell death in neurons. Chemicals that affect cholesterol homeostasis should therefore be regarded as possible developmental neurotoxicants with the potential of producing devastating effects in the developing brain. Although in recent years intense research was devoted to investigate the effects of genetic disorders on brain cholesterol homeostasis, very few studies have investigated the effects of developmental neurotoxicants on brain cholesterol; therefore, this area is rich in opportunities for future studies.

Original languageEnglish (US)
Title of host publicationReproductive and Developmental Toxicology
PublisherElsevier
Pages1077-1088
Number of pages12
ISBN (Electronic)9780128042397
DOIs
StatePublished - Jan 1 2017

Keywords

  • ATP-binding cassette cholesterol transporters
  • Brain development
  • Cholesterol
  • Ethanol
  • Fetal alcohol spectrum disorders
  • Lipoproteins
  • Neurodevelopmental disorders
  • Retinoic acid
  • Retinoic acid embryopathy
  • Smith-Lemli-Opitz syndrome

ASJC Scopus subject areas

  • Medicine(all)

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