Biology subjects

Karkkainen, O.

Publications and source records attributed to Karkkainen, O..

3 recordsLinked to original sources

bioRxiv2024

Effects of alcohol on the transcriptome, methylome, and metabolome of in vitro gastrulating human embryonic cells

Prenatal alcohol exposure (PAE) affects embryonic development, causing a variable fetal alcohol spectrum disorder (FASD) phenotype with neurodevelopmental disorders and birth defects. To explore the effects of PAE on gastrulation, we used an in vitro model with subchronic moderate (20 mM) and severe (70 mM) ethanol exposures during the differentiation of human embryonic stem cells into germ layer cells. We analysed genome-wide gene expression (mRNA sequencing), DNA methylation (EPIC Illumina microarrays), and metabolome (non-targeted LC-MS method) of the endodermal, mesodermal, and ectodermal cells. The largest number of ethanol-induced alterations were observed in the endodermal cells, whereas the most prominent changes were seen in the ectodermal cells. Genes of the major morphogen signaling pathways involved in gastrulation and body patterning were affected by ethanol. Many of the altered genes, such as BMP4, FGF8, SIX3, and LHX2, have been previously associated with PAE and phenotypes of FASD, like defects in heart and corpus callosum development as well as holoprosencephaly. Furthermore, methionine metabolism was altered in all germ layer cells. Our findings support the early origin of alcohol-induced developmental disorders and strengthen the role of methionine cycle in the etiology of FASD.

genetics↗

bioRxiv2022

Impacts of maternal microbiota and microbial metabolites on fetal intestine, brain and placenta

The maternal microbiota modulates fetal development, but the mechanisms of these earliest host-microbe interactions are unclear. We compared full-term fetuses from germ-free (GF) and normally colonized mouse dams by gene expression profiling and non-targeted metabolomics. The developing immune system was strongly dependent on the maternal microbial status. In the fetal intestine, critical components mediating host-microbe interactions were differentially expressed. In fetal brain and placenta, interferon and inflammatory signaling were downregulated in germ-free fetuses. Neural system development and function, translation and RNA metabolism, and regulation of energy metabolism were significantly affected at the gene expression level. These impacts were strongly associated with microbial metabolite concentrations in the fetal tissues, suggesting that they are largely, although perhaps not exclusively mediated by maternal microbial metabolites absorbed through placenta. Several aryl sulfates were among the compounds strongly associated with gene expression differences. The germ-free fetus may suffer from depletion of queuine, a bacterial hypermodified nucleobase essential for eukaryotic tRNA stability and function.

microbiology↗

bioRxiv2021

Physiological basis underlying antidepressant-induced activation of TrkB receptors

We show that both pharmacological and non-pharmacological treatments of depression activate TrkB receptors--a well-established target of antidepressants--by inducing a physiological response coupled to sedation. Several rapid-acting antidepressants trigger TrkB signaling by evoking a state associated with electroencephalographic slow-wave activity, behavioral immobility, reduced cerebral glucose utilization, and lowered body temperature. Remarkably, antidepressant-induced TrkB signaling was not compromised in animals exhibiting reduced activity-dependent release of BDNF but was diminished by maintaining animals in warm ambient temperature. Most importantly, prevention of the hypothermic response attenuated the behavioral effects produced by rapid-acting antidepressant nitrous oxide. Our results suggest that the phenomenon underlying TrkB transactivation--changes in energy expenditure and thermoregulation--is essential, but not sufficient, for antidepressant responses. Indeed, regardless of differential clinical and pharmacodynamic properties, all drugs that disrupt energy metabolism and induce hypothermia activated TrkB. This study challenges pharmacology-centric hypotheses regarding antidepressant effects and highlight the role of complex changes in bioenergetics and thermoregulation. HighlightsO_LIRapid-acting antidepressants evoke homeostatic emergence of slow-wave sleep during which TrkB signaling becomes regulated. C_LIO_LINon-antidepressant metabolic inhibitors and diverse sedatives activate TrkB signaling. C_LIO_LIReduction in body temperature determined the ability of antidepressants to transactivate TrkB. C_LIO_LIDrug-induced TrkB signaling was blunted by maintenance of normothermic body temperature. C_LIO_LIWarm ambient temperature after nitrous oxide exposure blocked the antidepressant-like effects. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/458151v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1f7351borg.highwire.dtl.DTLVardef@bf920forg.highwire.dtl.DTLVardef@10e34eaorg.highwire.dtl.DTLVardef@1b42bb6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗