The neurobehavioral teratology of retinoids: A 50‐year history

Abstract

This review of the central nervous system (CNS) and behavioral teratology of the retinoids over the last 50 years is a commemorative retrospective organized by decade to show the prominent research focus within each period and the most salient findings. In the 1960s, research focused on the gross CNS malformations associated with exposure and the delineation of dose-response and stage-specific responses in rodent models. Relevant scientific events before and during the 1960s are also discussed to provide the zeitgeist in which the field of neurobehavioral teratology emerged in the 1970s. During this period, studies demonstrated that adverse effects on postnatal behavior could be produced in animals exposed to doses of vitamin A lower than those that were teratogenic or impacted growth. Work during the 1980s showed an overrepresentation of behavioral studies focused on the reliability of screening methods, while the marked effects of human exposure were illustrated in children born to women treated with isotretinoin during pregnancy. The human catastrophe invigorated research during the 1990s, a period when technological advances allowed more elegant examinations of the developing CNS, of biochemical, cellular, and molecular developmental events and regulatory actions, and of the effects of direct genetic manipulations. Likewise, research in the 1990s reflected a reinvigoration of research in neurobehavioral teratology evinced in studies that used animal models to try to better understand human vulnerability. These foci continued in the 2000-2010 period while examinations of the role of retinoids in brain development and lifelong functioning became increasingly sophisticated and broader in scope. This review of the work on retinoids also provides a lens on the more general ontogeny of the field of neurobehavioral teratology. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Persistent behavioral effects following early life exposure to retinoic acid or valproic acid in zebrafish

“…Adams, 2010) pertaining to the social and emotional consequences of retinoid disruption. As early as the 1950’s, animal studies have associated specific malformations (e.g.…”

“…In particular, excess vitamin A during early development results in gross neural malformations, including neural tube defects, newborn lethality, growth reduction, and behavioral dysfunction in experimental animals (Steele et al, 1983; Shenefelt, 1972; for a review see Adams, 1993 or Adams, 2010). Early work in this field characterized the persisting effects of disrupted retinoid signaling on behavior and cognition, which can occur in the absence of overt toxicity or physical malformation (see Vorhees et al, 1978; 1979; for a review see Adams, 2010). In the late 1990’s, the theory that autism spectrum disorder may arise from gestational events at the time of neural tube closure (e.g.…”

Cracking the Egg: Potential of the Developing Chicken as a Model System for Nonclinical Safety Studies of Pharmaceuticals

“…Retinoids are known teratogens that also affect the nervous system in the human embryo (Adams, 2010). Here, there is good concordance between the chicken and other animal models.…”

Dermatological medications and local therapeutics

“…With the reported risk of 30% birth defects, they have a tenfold higher risk for major birth defects if used systemically during the first trimester. Follow-up examination of 5-to 10-year-old children with intrauterine exposure showed an increased rate of mental retardation and special weaknesses in visual-spatial processing and this, to some extent, also among children without major visible birth defects (Adams 2010).…”

“…Their use during pregnancy increases the risk of spontaneous abortion and leads to the characteristic retinoid syndrome: anomalies of the ears, including agenesis or stenosis of the auditory canal, facial and palatine defects, micrognathia, cardiovascular defects and developmental defects of the thymus and the central nervous system which can range from involvement of the eyes and the inner ear to hydrocephalus (Lammer 1985(Lammer , 1988. Intelligence deficits have also be observed even in children without recognizable birth defects (Adams 2010). With the reported risk of 30% birth defects, they have a tenfold higher risk for major birth defects if used systemically during the first trimester.…”