Maternal choline supplementation in a sheep model of first trimester binge alcohol fails to protect against brain volume reductions in peripubertal lambs

Abstract

Fetal alcohol spectrum disorder (FASD) is a leading potentially preventable birth defect. Poor nutrition may contribute to adverse developmental outcomes of prenatal alcohol exposure, and supplementation of essential micronutrients such as choline has shown benefit in rodent models. The sheep model of first-trimester binge alcohol exposure was used in this study to model the dose of maternal choline supplementation used in an ongoing prospective clinical trial involving pregnancies at risk for FASD. Primary outcome measures included volumetrics of the whole brain, cerebellum, and pituitary derived from magnetic resonance imaging (MRI) in 6-month-old lambs, testing the hypothesis that alcohol-exposed lambs would have brain volume reductions that would be ameliorated by maternal choline supplementation. Pregnant sheep were randomly assigned to one of five groups – heavy binge alcohol (HBA; 2.5 g/kg/treatment ethanol), heavy binge alcohol plus choline supplementation (HBC; 2.5 g/kg/treatment ethanol and 10 mg/kg/day choline), saline control (SC), saline control plus choline supplementation (SCC; 10 mg/kg/day choline), and normal control (NC). Ewes were given intravenous alcohol (HBA, HBC; mean peak BACs of ~280 mg/dL) or saline (SC, SCC) on three consecutive days per week from gestation day (GD) 4–41; choline was administered on GD 4–148. MRI scans of lamb brains were performed postnatally on day 182. Lambs from both alcohol groups (with or without choline) showed significant reductions in total brain volume; cerebellar and pituitary volumes were not significantly affected. This is the first report of MRI-derived volumetric brain reductions in a sheep model of FASD following binge-like alcohol exposure during the first trimester. These results also indicate that maternal choline supplementation comparable to doses in human studies fails to prevent brain volume reductions typically induced by first-trimester binge alcohol exposure. Future analyses will assess behavioral outcomes along with regional brain and neurohistological measures.

Effects of Early Alcohol Exposure on Functional Organization and Microstructure of a Visual‐Tactile Integrative Circuit

“…Volume reductions were shown to be associated with behavioral impairments(Stevens and Haney-Caron, 2012, Chiang et al, 2007). As was observed in the present animal study, reduction of overall brain size of prenatal alcohol exposed subjects has been repeatedly reported in postmortem studies as well as in neuroimaging studies(Wisniewski et al, 1983, Archibald et al, 2001, Birch et al, 2016). In addition to the reduction of overall brain size, the absolute volumes of various brain cortical and subcortical areas were consistently reduced in humans with prenatal exposure to alcohol(Chen et al, 2012, Rajaprakash et al, 2014, Archibald et al, 2001).…”

Effect of Choline Supplementation on Neurological, Cognitive, and Behavioral Outcomes in Offspring Arising from Alcohol Exposure During Development: A Quantitative Systematic Review of Clinical and Preclinical Studies

“…Measurement of serum choline levels, either pre‐ or postintervention, was not included in any of the rodent preclinical studies. However, serum choline was measured in the sheep trial (Birch et al., ) and was confirmed to be lowered by EtOH compared to controls and increased by choline supplementation. Wozniak and colleagues () confirmed that serum choline levels were raised by the choline intervention, but as all participants had been exposed to alcohol, baseline serum choline levels could not indicate whether there was an underlying deficiency compared to nonexposed individuals.…”

Prenatal Amino Acid Supplementation to Improve Fetal Growth: A Systematic Review and Meta-Analysis

“…We included 30 animal studies (mice n = 3 [ 106 , 107 , 108 ]; rats n = 14 [ 43 , 97 , 98 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 ]; guinea pigs n = 4 [ 120 , 121 , 122 , 123 ]; rabbits = 1 [ 124 ]; sheep n = 3 [ 125 , 126 , 127 ]; and cows n = 5 [ 128 , 129 , 130 , 131 , 132 ]) and 6 human studies [ 133 , 134 , 135 , 136 , 137 , 138 ] reporting on fetal growth in response to prenatal methyl donor supplementation. In 16 of these studies, methionine was used [ 43 , 97 , 98 , 115 , 116 , 117 , 118 , 119 , 123 , 124 , …”