Format

Send to

Choose Destination
Am J Obstet Gynecol. 2016 May;214(5):623.e1-623.e10. doi: 10.1016/j.ajog.2016.02.054. Epub 2016 Mar 3.

Males are from Mars, and females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity.

Author information

1
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Tufts Medical Center, Boston, MA; Mother Infant Research Institute, Tufts Medical Center, Boston, MA. Electronic address: aedlow@tuftsmedicalcenter.org.
2
Mother Infant Research Institute, Tufts Medical Center, Boston, MA.
3
National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
4
Mother Infant Research Institute, Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA.
5
Division of Genetics, Department of Pediatrics, Floating Hospital for Children, Boston, MA.

Abstract

BACKGROUND:

Maternal obesity is associated with adverse neurodevelopmental outcomes in children, including autism spectrum disorders, developmental delay, and attention-deficit hyperactivity disorder. The underlying mechanisms remain unclear. We previously identified second-trimester amniotic fluid and term cord blood gene expression patterns suggesting dysregulated brain development in fetuses of obese compared with lean women.

OBJECTIVE:

We sought to investigate the biological significance of these findings in a mouse model of maternal diet-induced obesity. We evaluated sex-specific differences in fetal growth, brain gene expression signatures, and associated pathways.

STUDY DESIGN:

Female C57BL/6J mice were fed a 60% high-fat diet or 10% fat control diet for 12-14 weeks prior to mating. During pregnancy, obese dams continued on the high-fat diet or transitioned to the control diet. Lean dams stayed on the control diet. On embryonic day 17.5, embryos were weighed and fetal brains were snap frozen. RNA was extracted from male and female forebrains (10 per diet group per sex) and hybridized to whole-genome expression arrays. Significantly differentially expressed genes were identified using a Welch's t test with the Benjamini-Hochberg correction. Functional analyses were performed using ingenuity pathways analysis and gene set enrichment analysis.

RESULTS:

Embryos of dams on the high-fat diet were significantly smaller than controls, with males more severely affected than females (P = .01). Maternal obesity and maternal obesity with dietary change in pregnancy resulted in significantly more dysregulated genes in male vs female fetal brains (386 vs 66, P < .001). Maternal obesity with and without dietary change in pregnancy was associated with unique brain gene expression signatures for each sex, with an overlap of only 1 gene. Changing obese dams to a control diet in pregnancy resulted in more differentially expressed genes in the fetal brain than maternal obesity alone. Functional analyses identified common dysregulated pathways in both sexes, but maternal obesity and maternal dietary change affected different aspects of brain development in males compared with females.

CONCLUSION:

Maternal obesity is associated with sex-specific differences in fetal size and fetal brain gene expression signatures. Male fetal growth and brain gene expression may be more sensitive to environmental influences during pregnancy. Maternal diet during pregnancy has a significant impact on the embryonic brain transcriptome. It is important to consider both fetal sex and maternal diet when evaluating the effects of maternal obesity on fetal neurodevelopment.

KEYWORDS:

diet; fetal programming; growth; maternal obesity; neurodevelopment; sex differences; transcriptome

PMID:
26945603
PMCID:
PMC4851594
DOI:
10.1016/j.ajog.2016.02.054
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center