(Sept. 24, 2012) -- In collaboration with scholars at the University of Hawaii and the University of Pennsylvania School of Medicine, a group of researchers led by John McCarrey, the UTSA College of Sciences' Kleberg Distinguished Chair in Cellular and Molecular Biology, and his graduate student Eric de Waal, who recently received his Ph.D. degree from UTSA, have demonstrated that the hormones known as gonadotropins lead to an increase in epimutations in mice produced in vitro.
The findings are important because they call into question the safety of the methods that are commonly used when couples use the in vitro fertilization process to have children.
The epigenome is the mechanism that programs the genome to control gene expression in each type of cell, and this ultimately decides one's outward appearance and influences development. Epimutations can lead to changes in appearance, development or cellular function when they disrupt the normal function of one or more genes in a cell.
Assisted reproductive technologies (ART) such as in vitro fertilization are a commonly accepted practice and account for more than four million children born worldwide so far, however caution persists among some scholars who point out that the long-term safety of these methods remains generally unknown. Most of the people conceived with the help of ART are currently still under the age of 35.
To better understand how ART and epimutations are linked, the scholars compared the frequency of epimutations in mice produced through an ART process called intracytoplasmic sperm injection (ICSI). They found the epimutation rate to be elevated in mice produced by this method when compared to that in naturally conceived mice.
Next, they compared the frequency of epimutations in three groups of mice: (1) mice produced by natural conception, (2) ICSI-derived mice and (3) mice derived through a process called somatic cell nuclear transfer (SCNT), also known as "cloning". They expected the epimutation rates in the cloned SCNT-derived mice to be higher than those in the ICSI mice. They were surprised, however, to find that the ICSI-derived mice had a higher rate of epimutations than the SCNT-derived mice.
The scholars then reasoned that since gonadotropin-stimulated eggs were used to produce both the ICSI and SCNT-derived offspring, but the nucleus in the egg used for SCNT was then replaced with another nucleus that had not been stimulated with gonadotropin, the lingering effects of gonadotropin exposure in the ICSI-derived offspring must be related to the higher incidence of epimutations in these mice. To test this idea, they subjected female mice to gonadotropin stimulation and then allowed the mice to reproduce naturally to isolate the effects of gonadotropins.
Ultimately, they found that the offspring produced from females subjected to gonadotropin stimulation displayed the same elevated incidence of epimutations they observed in the mice produced by ICSI, confirming that gonadotropin stimulation is a significant factor in inducing epimuations.
Although the mouse sample size the researchers used was small, McCarrey says the findings warrant some caution about the methods associated with ART and call for additional study to determine if the findings hold true in humans.
"ART now accounts for one to four percent of all births in developed countries, so we must work to make this process as completely safe as possible" said McCarrey. "Our results suggest that gonadotropin stimulation, which is typically used in every ART procedure, contributes to the formation of epimutations in the offspring produced. We want to understand why this happens, how it happens and what long-term effects this causes."
The research is available in Human Molecular Genetics.
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