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Transgenerational Effects of Antenat...

Constantinof, Andrea.

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Transgenerational Effects of Antenatal Synthetic Glucocorticoid Exposure on Transcription and Methylation in the Developing Brain.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Transgenerational Effects of Antenatal Synthetic Glucocorticoid Exposure on Transcription and Methylation in the Developing Brain./
Author:	Constantinof, Andrea.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	185 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-01, Section: B.
Contained By:	Dissertations Abstracts International80-01B.
Subject:	Neurosciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10749988
ISBN:	9780438187542

Transgenerational Effects of Antenatal Synthetic Glucocorticoid Exposure on Transcription and Methylation in the Developing Brain.
Constantinof, Andrea.

Transgenerational Effects of Antenatal Synthetic Glucocorticoid Exposure on Transcription and Methylation in the Developing Brain. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 185 p.

Source: Dissertations Abstracts International, Volume: 80-01, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2018.

This item is not available from ProQuest Dissertations & Theses.

The early environment has long term influences on future health that are heritable over multiple generations via maternal and paternal lineages. Antenatal synthetic glucocorticoids (sGC) are administered to women at risk for pre-term delivery because they reduce the morbidity and mortality associated with newborn respiratory distress syndrome. However, the administration of multiple courses of antenatal sGC results in long-term programing of behavioral and physiological responses to stress. In this research, we performed transcriptomic and epigenomic analyses to ascertain the long-term programming effects of antenatal sGC in the brains of first generation (F1) juvenile males and three generations of juvenile female offspring of the paternal lineage. We hypothesized that antenatal sGC exposure results in transgenerational changes in transcription and DNA methylation in the hypothalamic paraventricular nucleus (PVN), prefrontal cortex (PFC) and hippocampus, due to their role in the regulation of the HPA-axis. We observed that antenatal sGC results in generation-, sex-, and brain region-specific changes in gene expression and DNA methylation in three generations juvenile female offspring of the paternal lineage. In the PVN, exposure to sGC programmed large transgenerational changes in gene expression, including type II diabetes, thermoregulation, and collagen formation gene networks. The PFC was the only brain region to show overlap in the significantly differentially expressed genes across all three generations of juvenile females and F1 males. In the PFC, the expression of four genes that were significantly decreased in sGC offspring explained 20-29% of the variability in locomotor behavioral phenotypes. Epigenetic analyses of the hippocampus identified significant changes in CpG methylation in regulatory regions of small non-coding RNAs involved in transcription and splicing. These findings may implicate alternative splicing as a mechanism involved in the transgenerational transmission of the effects of antenatal sGC. This is the first study to show that antenatal sGC exposure, a clinically relevant treatment, results in transgenerational changes in gene expression, and methylation over three generations, via paternal transmission.

ISBN: 9780438187542Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

Epigenetics

Transgenerational Effects of Antenatal Synthetic Glucocorticoid Exposure on Transcription and Methylation in the Developing Brain.
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520 $a The early environment has long term influences on future health that are heritable over multiple generations via maternal and paternal lineages. Antenatal synthetic glucocorticoids (sGC) are administered to women at risk for pre-term delivery because they reduce the morbidity and mortality associated with newborn respiratory distress syndrome. However, the administration of multiple courses of antenatal sGC results in long-term programing of behavioral and physiological responses to stress. In this research, we performed transcriptomic and epigenomic analyses to ascertain the long-term programming effects of antenatal sGC in the brains of first generation (F1) juvenile males and three generations of juvenile female offspring of the paternal lineage. We hypothesized that antenatal sGC exposure results in transgenerational changes in transcription and DNA methylation in the hypothalamic paraventricular nucleus (PVN), prefrontal cortex (PFC) and hippocampus, due to their role in the regulation of the HPA-axis. We observed that antenatal sGC results in generation-, sex-, and brain region-specific changes in gene expression and DNA methylation in three generations juvenile female offspring of the paternal lineage. In the PVN, exposure to sGC programmed large transgenerational changes in gene expression, including type II diabetes, thermoregulation, and collagen formation gene networks. The PFC was the only brain region to show overlap in the significantly differentially expressed genes across all three generations of juvenile females and F1 males. In the PFC, the expression of four genes that were significantly decreased in sGC offspring explained 20-29% of the variability in locomotor behavioral phenotypes. Epigenetic analyses of the hippocampus identified significant changes in CpG methylation in regulatory regions of small non-coding RNAs involved in transcription and splicing. These findings may implicate alternative splicing as a mechanism involved in the transgenerational transmission of the effects of antenatal sGC. This is the first study to show that antenatal sGC exposure, a clinically relevant treatment, results in transgenerational changes in gene expression, and methylation over three generations, via paternal transmission.
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