Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders.

BACKGROUND: Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neuronal disorders and birth defects. We hypothesize that early alcohol-induced epigenetic changes disrupt the accurate developmental programming of embryo and consequently cause the complex phenotype of developmental disorders. To explore the etiology of FASD, we collected unique biological samples of 80 severely alcohol-exposed and 100 control newborns at birth. METHODS: We performed genome-wide DNA methylation (DNAm) and gene expression analyses of placentas by using microarrays (EPIC, Illumina) and mRNA sequencing, respectively. To test the manifestation of observed PAE-associated DNAm changes in embryonic tissues as well as potential biomarkers for PAE, we examined if the changes can be detected also in white blood cells or buccal epithelial cells of the same newborns by EpiTYPER. To explore the early effects of alcohol on extraembryonic placental tissue, we selected 27 newborns whose mothers had consumed alcohol up to gestational week 7 at maximum to the separate analyses. Furthermore, to explore the effects of early alcohol exposure on embryonic cells, human embryonic stem cells (hESCs) as well as hESCs during differentiation into endodermal, mesodermal, and ectodermal cells were exposed to alcohol in vitro. RESULTS: DPPA4, FOXP2, and TACR3 with significantly decreased DNAm were discovered-particularly the regulatory region of DPPA4 in the early alcohol-exposed placentas. When hESCs were exposed to alcohol in vitro, significantly altered regulation of DPPA2, a closely linked heterodimer of DPPA4, was observed. While the regulatory region of DPPA4 was unmethylated in both control and alcohol-exposed hESCs, alcohol-induced decreased DNAm similar to placenta was seen in in vitro differentiated mesodermal and ectodermal cells. Furthermore, common genes with alcohol-associated DNAm changes in placenta and hESCs were linked exclusively to the neurodevelopmental pathways in the enrichment analysis, which emphasizes the value of placental tissue when analyzing the effects of prenatal environment on human development. CONCLUSIONS: Our study shows the effects of early alcohol exposure on human embryonic and extraembryonic cells, introduces candidate genes for alcohol-induced developmental disorders, and reveals potential biomarkers for prenatal alcohol exposure.

Brain magnetic resonance imaging of infants exposed prenatally to buprenorphine.

PURPOSE: To evaluate the brains of newborns exposed to buprenorphine prenatally. MATERIAL AND METHODS: Seven neonates followed up antenatally in connection with their mothers' buprenorphine replacement therapy underwent 1.5 T magnetic resonance imaging (MRI) of the brain before the age of 2 months. The infants were born to heavy drug abusers. Four mothers were hepatitis C positive, and all were HIV negative. All mothers smoked tobacco and used benzodiazepines. All pregnancies were full term, and no perinatal asphyxia occurred. All but one neonate had abstinence syndrome and needed morphine replacement therapy. RESULTS: Neither structural abnormalities nor abnormalities in signal intensity were recorded. CONCLUSION: Buprenorphine replacement therapy does not seem to cause any major structural abnormalities of the brain, and it may prevent known hypoxic-ischemic brain changes resulting from uncontrolled drug abuse. Longitudinal studies are needed to assess possible abnormalities in the brain maturation process.

Regional distribution of functions in dorsolateral prefrontal cortex of the the monkey.

Single-cell responses were obtained from 352 neurons in dorsolateral prefrontal cortex (Walker's areas 9 and 46) of three monkeys. The neurons were classified functionally according to their responsiveness to visual, auditory and somatosensory stimulation, and to correlation of their activity with spontaneous eye or limb movements. A comparison between the distribution of different functions and known modality-specific anatomical connections to various sectors of this area showed a good correspondence. On average somatosensory and motor neurons were located more ventrally than the remaining ones, and were concentrated to the middle third of the inferior bank of principal sulcus and adjacent inferior convexity, where a number of somatosensory projections overlap. Oculomotor neurons were found caudally in both banks of principal sulcus and in a narrow band on the dorsal convexity, coinciding with the projection fields of areas 7a and 7ip of posterior parietal cortex, superior colliculus, and paramedian pontine tegmentum. Other functions were scatteredly distributed. Visual neurons which preferred moving to stationary stimuli were located more caudally and dorsally than other visual neurons. The present study shows that a parcellation of dorsolateral prefrontal cortex proposed on the basis of anatomical connectivity is also functionally evident.

Functional properties of dorsolateral prefrontal cortical neurons in awake monkey.

Electrophysiological single-cell responses were studied in 134 neurons in Walker's areas 46 and 9 of the prefrontal cortex of two stumptail macaques. The neurons were systematically tested for various visual, auditory and somatosensory stimuli. In addition, the rate of neuronal discharges were observed in relation to provoked or spontaneous eye or limb movements. More than half (52.2%) of the neurons responded to stimulation, and the majority of them gave visual responses. Eighty percent of the visual neurons responded to the presentation of various objects, the remaining being selective for meaningful objects or the appearance and movements of the experimenter. Auditory, somatosensory, somatomotor and oculomotor responses were also encountered; 9.0% of the recorded neurons were multimodal. Despite the large stimulus repertoire 47.8% of the neurons were found to be only spontaneously active.