title: Low and moderate prenatal ethanol exposures of mice during gastrulation or neurulation delays neurobehavioral development.
abstract: Human and animal studies show significant delays in neurobehavioral development in offspring after prolonged prenatal exposure to moderate and high ethanol doses resulting in high blood alcohol concentration (BECs). However, none have investigated the effects of lower ethanol doses given acutely during specific developmental time periods. Here, we sought to create a mouse model for modest and circumscribed human drinking during the 3rd and 4th weeks of pregnancy. We acutely treated mice during embryo gastrulation on gestational day (GD) 7 or neurulation on GD8 with a low or moderate ethanol dose given via gavage that resulted in BECs of 107 and 177 mg/dl, respectively. We assessed neonatal physical development (pinnae unfolding, and eye opening); weight gain from postnatal day (PD) 3-65; and neurobehavioral maturation (pivoting, walking, cliff aversion, surface righting, vertical screen grasp, and rope balance) from PD3 to 17. We used a multiple linear regression model to determine the effects of dose, sex, day of treatment and birth in animals dosed during gastrulation or neurulation, relative to their vehicle controls. We found that ethanol exposure during both time points (GD7 and GD8) resulted in some delays of physical development and significant sensorimotor delays of pivoting, walking, and thick rope balance, as well as additional significant delays in cliff aversion and surface righting after GD8 treatment. We also found that treatment with the low ethanol dose more frequently affected neurobehavioral development of the surviving pups than treatment with the moderate ethanol dose, possibly due to a loss of severely affected offspring. Finally, mice born prematurely were delayed in their physical and sensorimotor development. Importantly, we showed that brief exposure to low dose ethanol, if administered during vulnerable periods of neuroanatomical development, results in significant neurobehavioral delays in neonatal mice. We thus expand concerns about alcohol consumption during the 3rd and 4th weeks of human pregnancy to include occasional light to moderate drinking.
authors.affiliation: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. Electronic address: schambra@etsu.edu.
authors.forename: Uta B
authors.initials: UB
authors.lastname: Schambra
authors.affiliation: Columbia Mailman School of Public Health, Department of Biostatistics, New York, NY 10023, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Goldsmith
authors.affiliation: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Nunley
authors.affiliation: Department of Mathematics & Statistics, College of Arts and Sciences, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Harirforoosh
authors.affiliation: Department of Rehabilitation & Regenerative Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Schambra
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000097:blood / Q000633:toxicity*; D002658:Developmental Disabilities / Q000139:chemically induced*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000097:blood / Q000633:toxicity*; D005260:Female; D054262:Gastrulation / Q000187:drug effects*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000187:drug effects; D054261:Neurulation / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D011930:Reaction Time / Q000187:drug effects; D012678:Sensation Disorders / Q000139:chemically induced
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol
keywords: Gastrulation; Low ethanol dose; Moderate ethanol dose; Mouse; Neurobehavioral delays; Neurulation; Premature birth; Sensorimotor development