Candidate genes for ART- and subfertility-associated phenotypes

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Who are we?

Our Environmental Epigenetics Laboratory locates at the University of Helsinki in Finland. We aim to understand how our phenotypes are formed by our genome, early life environment and stochastic events. Our focus is on the epigenome and its role as a mediator of environmental influences. By collecting cohorts together with our collaborators in the Helsinki University Hospital, we are studying the effects of prenatal alcohol exposure, assisted reproductive technologies (ART) and subfertility on embryonic development and life long health.

 

Our study and key findings

Approximately one in six couples trying to have a child experiences infertility, and to date, over ten million children worldwide have been conceived by fertility treatments. Although they are generally healthy, ART has been associated with slightly increased risks for growth disturbance, disrupted imprinting as well as cardiovascular, metabolic, and neurodevelopmental disorders. In the current study, we aimed to clarify ART-associated  molecular alterations in placenta as well as their potential association with the anthropometric measurements of ART derived newborns. However, ART pregnancies are not a homogeneous group, but differ from each other due to the procedures, causes of underlying subfertility and sex of the child. Therefore, for the first time, we performed separate genome-wide DNA methylation and gene expression analyses for placentas from different ART procedures, intrauterine insemination and natural conceptions of subfertile couples. Also, sex-specific analyses were conducted. Here are our most interesting discoveries in brief:

1) ART-associated placental changes were linked to genes in pathways of hormonal regulation, insulin secretion, neurodevelopment and vascularization, corresponding to ART-related phenotypes.

2) Changes in the genes associated with growth and metabolism were more clearly linked to fresh embryo transfer with smaller placentas and newborns than to frozen embryo transfer with larger placentas and newborns. This could be explained by hormonal disturbances caused by ovarian stimulation in the pregnancies with freshly transferred embryos.

3) Only a low number of in vitro culture-associated changes were seen, suggesting a stronger impact of the underlying subfertility and hormonal treatments on the gene function.

4) In ICSI-derived placentas, where intracytoplasmic sperm injection was included in in vitro fertilization, changes in genes associated with male infertility were observed on the Y chromosome. This may provide a clue to the causes of paternal subfertility, as male factor infertility was a prominent reason for the use of ICSI procedure in this study. Interestingly, the altered genes clustered to the pathway of “response to toxic substances”, suggesting that the placenta could provide a molecular window even to germ cells.

5) We found excellent candidate genes, TRIM28, NOTCH3 and DLK1, whose decreased expression could contribute to the ART-associated phenotypes with increased risk for growth disturbances, metabolic changes, and unstability of the imprinting. Interestingly, TRIM28 is a known stabilizer of imprinting and a regulator of DLK1 expression.

6) One of the most interesting genes was the imprinted  DLK1, which associated with both ART and subfertility. According to previous studies, it inhibits adipogenesis and is essential for maternal metabolic adaptation to pregnancy. In human, mutations in DLK1 gene have been reported as a cause of prenatal growth failure, short postnatal stature, female early onset puberty, metabolic syndrome and truncal obesity. Since increased risks for newborns who are small for gestational age, rapid postnatal growth, and female early onset puberty have all been associated with ART children in previous studies, DLK1 is a plausible candidate gene for the ART phenotype. Future studies should be focused on its role in the increased ART- and subfertility-associated risks for low birth weight as well as metabolic disorders later in life.

Why placental tissue?

The placenta has proven to be an extremely fascinating organ which connects the mother and the fetus, mediates environmental effects on the fetus and influences fetal development. It offers a unique window into the gene function during very early developmental stages, which are otherwise difficult to study in human. Although we managed to reveal exciting candidate genes and pathways associated with ART procedures and subfertility, larger sample sizes are needed for more detailed subgroup- and sex-specific analyses. Luckily, our cohorts continue to grow, and we want to thank all the families who participated in the study.

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Follow the Topic

Epigenetics
Life Sciences > Biological Sciences > Molecular Biology > Epigenetics
Reproductive Medicine
Life Sciences > Health Sciences > Clinical Medicine > Reproductive Medicine
Infertility
Life Sciences > Health Sciences > Clinical Medicine > Diseases > Reproductive Disorders > Infertility
Assisted Reproductive Techniques
Life Sciences > Health Sciences > Clinical Medicine > Therapeutics > Assisted Reproductive Techniques
Genetic Imprinting
Life Sciences > Biological Sciences > Genetics and Genomics > Epigenetics > Genetic Imprinting

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