- Project 2 Although controversial, epidemiologic studies have indicated that conception through assisted reproductive technologies (ART), such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), presents a risk for autism spectrum disorders (ASD) and other neurological defects. ART has also been implicated in mediating long-term epigenetic dysregulation, thereby contributing to developmental diseases in humans. To date, genetic variance accounts for fewer than 10% of examined ASD cases, reinforcing the notion that environmental and epigenetic factors underlie ASD incidence. Indeed, culture conditions used in current ART procedures appear to modify epigenetic patterns of normal embryonic development. Additionally, we have identified a potential candidate gene, Shank3, whose genetic and/or epigenetic disruption associates with ASD-like phenotypes in mice. However, the extent to which epigenetic dysregulation directly underlies the ART-associated increased risk for ASD remains undetermined. This is in part due to the lack of a gene-by- environment model relevant to ASD or other neurological disorders. To address this, massively parallel high- throughput sequencing technologies will be employed to examine and characterize the DNA methylomes and gene transcriptomes of brain from IVF-, ICSI-, and naturally-conceived mice (Aim 1). Additionally, comprehensive behavioral assessments will be performed on all mice to link observed epigenetic alterations with social and/or cognitive impairments that characterize ASD (Aim 2). By integrating the genome-wide datasets with behavioral information, candidate ART-associated biomarker genes that are epigenetically dysregulated, including Shank3, will be identified and further investigated during the course of embryonic and brain development (Aim 3). Collectively, addressing these proposed aims will yield a detailed, temporally- defined gene network that underscores the relationship between the pre-implantation environment and the epigenetic mechanisms that play critical roles in neurodevelopment, and help establish a gene-by-environment model of ASD for future investigation to better understand its etiology. Importantly, data from this study will lay the foundation for objectively and rationally altering current ART methodologies to reduce the penetrance of ART-associated ASD and related neurological defects in humans. This work is therefore consistent with the mission of NIH/NIGMS in that it will add to the fundamental knowledge about how the environment of early development may alter normal epigenetic processes that adversely impact long-term health and establishes a novel model that can be applied to inform clinical practices.

Public Health Relevance

- Project 2 This research promises to strengthen our basic understanding of the epigenetic events important to brain development that follow fertilization and examines the controversial link between assisted reproductive technologies and autism. A novel gene-by-environment model will be established as a result of this study, to guide clinical practices modified to reduce the frequency of unintended developmental disorders, particularly autism, in children conceived through the use of assisted reproductive technologies.

Agency
National Institute of Health (NIH)
Type
Exploratory Grants (P20)
Project #
2P20GM103457-06A1
Application #
8737528
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Hawaii
Department
Type
DUNS #
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Kono, Kanako; Tamashiro, Dana Ann A; Alarcon, Vernadeth B (2014) Inhibition of RHO-ROCK signaling enhances ICM and suppresses TE characteristics through activation of Hippo signaling in the mouse blastocyst. Dev Biol 394:142-55
Collier, Abby C; Yamauchi, Yasuhiro; Sato, Brittany L M et al. (2014) UDP-glucuronosyltransferase 1a enzymes are present and active in the mouse blastocyst. Drug Metab Dispos 42:1921-5
Comptour, Aurélie; Moretti, Charlotte; Serrentino, Maria-Elisabetta et al. (2014) SSTY proteins co-localize with the post-meiotic sex chromatin and interact with regulators of its expression. FEBS J 281:1571-84
Ching, Travers; Huang, Sijia; Garmire, Lana X (2014) Power analysis and sample size estimation for RNA-Seq differential expression. RNA 20:1684-96
Yamauchi, Yasuhiro; Riel, Jonathan M; Stoytcheva, Zoia et al. (2014) Two Y genes can replace the entire Y chromosome for assisted reproduction in the mouse. Science 343:69-72
Wu, Zhenfang; Xu, Zhiqian; Zou, Xian et al. (2013) Pig transgenesis by piggyBac transposition in combination with somatic cell nuclear transfer. Transgenic Res 22:1107-18
Riel, Jonathan M; Yamauchi, Yasuhiro; Sugawara, Atsushi et al. (2013) Deficiency of the multi-copy mouse Y gene Sly causes sperm DNA damage and abnormal chromatin packaging. J Cell Sci 126:803-13
Hirate, Yoshikazu; Hirahara, Shino; Inoue, Ken-Ichi et al. (2013) Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos. Curr Biol 23:1181-94
Gawecka, Joanna E; Marh, Joel; Ortega, Michael et al. (2013) Mouse zygotes respond to severe sperm DNA damage by delaying paternal DNA replication and embryonic development. PLoS One 8:e56385
Jaremko, Kate Lynn; Marikawa, Yusuke (2013) Regulation of developmental competence and commitment towards the definitive endoderm lineage in human embryonic stem cells. Stem Cell Res 10:489-502

Showing the most recent 10 out of 11 publications