Neuroanatomic and Neurochemical Abnormalities in Non‐human Primate Infants Exposed to Weekly Doses of Ethanol during Gestation

Abstract

Ethanol was orally administered once per week to 54 gravid pigtailed macaques (Macaca nemestrina) in doses of 0.0, 0.3, 0.6, 1.2, 1.8, 2.5 or 4.1 gm/kg from the 1st week in gestation or in doses of 2.5, 3.3 or 4.1 gm/kg from the 5th week. Mean maternal peak plasma ethanol concentrations (MPPEC's) ranged from 24 +/- 6 mg/dl at the 0.3 g/kg dose to 549 +/- 71 mg/dl at the 4.1 g/kg dose. Thirty-three live born infants were assessed for abnormalities of physical and behavioral development. Ocular pathology, neuropathologic and neurochemical assessements were done on 31 animals at 6 months postnatal age. Microphthalmia was noted in three of the 26 animals exposed to ethanol. Retinal ganglion cell loss was significantly associated with intra-uterine ethanol exposure. Microphthalmia and retinal ganglion cell loss was observed in both the delayed and full-gestational exposed animals. No structural anomalies were found in the brains via gross inspection or light microscopy. Chemical abnormalities in the striatal nuclei were identified. Striatal dopamine concentrations increased with increasing MPPEC exposure (0-249 mg/dl) among animals exposed weekly to ethanol throughout gestation. Striatal dopamine concentrations decreased with increasing MPPEC exposure (260-540 mg/dl) among animals whose weekly exposure to ethanol was delayed until the 5th week of gestation. The same pattern of association was also noted between MPPEC and ultrastructural alterations in the caudate nucleus. The extent of ultrastructural alterations increased with increasing MPPEC among the full-gestational exposed animals and decreased with increasing MPPEC among the delayed-dose animals.

Cerebellar Granule Cell Migration and the Effects of Alcohol

“…Abnormalities of growth are not altered appreciably by attempts to change environmental variables such as nutritional factors, home setting and the like. The most serious feature of the syndrome is disturbance of the central nervous system [90][91][92][93]95] . Microcephaly is present in nearly all cases, and this reflection of disturbed brain growth is accompanied by delayed neurologic development in approximately 90% of the cases [90,91,96] .…”

Computational models of ethanol‐induced neurodevelopmental toxicity across species: Implications for risk assessment

“…Morphology of corpus callosum including length and number of dendritic branches on G29 (Qiang et al, 2002) 8 Monkey Intubation of .3, .6, 1.2, 1.8, 2.5, or 4.1 g/kg weekly throughout gestation Infant neurobehavioral (WGTA), micropthalmia, retinal ganglion cell loss, motor development, stiatal and caudate dopamine at 6 months (Clarren et al, 1988(Clarren et al, , 1990 9 Monkey Voluntary consumption of .6 g/kg of 6.6% ethanol solution daily from E0-E50, E50-E135, or E0-E165 Infant behavioral assessment scale (IBAS), adolescent learning and behavior with nonmatching-tosample task (NMS) (Schneider et al, 2001a,b) 10 Human Mostly low socioeconomic status, inner city women between 1983 and 1986 in Pittsburgh (N 5 595), alcohol use assessed at each trimester of pregnancy and at 8, 18, 36 months, and 6 years postpartum Neurobehavioral assessment at 3, 6 and 10 yrs.…”

“…neurodevelopment (Clarren et al, 1988(Clarren et al, , 1990Schneider et al, 2001a,b). Although the monkey population examined by Clarren et al did not show significant deficits at the lower doses tested, they did note increased frequencies of aberrant scores on neurobehavioral tests as well as morphological abnormalities such as micropthalmia, retinal ganglion cell loss, and increased striatal and caudate dopamine levels.…”

Psychopharmacological interventions in fragile X syndrome, fetal alcohol syndrome, Prader-Willi syndrome, Angelman syndrome, Smith-Magenis syndrome, and velocardiofacial syndrome

“…The incidence of FAS, PFAS, and ARND combined is approximately 1 per 100 in the general population [Sampson et al, 1997]. The validity of ARND is supported by animal and human evidence, which has documented CNS structural abnormalities without facial dysmorphic features, even with relatively low alcohol intake or occasional binge drinking [Clarren et al, 1990;Mattson et al, 1996;Streissguth, 1997]. Significant alcohol exposure in utero causes a variety of structural and neurochemical changes in the brain, including a small cerebellum, corpus callosum, and caudate, which are linked to the behavior problems, particularly hyperactivity and the cognitive deficits seen in FAS and ARND [Mattson and Riley, 1995;Mattson et al, 1996;Mattson et al, 1997].…”