Fertility Treatment Fallout

Mouse offspring conceived by in vitro fertilization are metabolically different from naturally conceived mice.

By | January 1, 2015

CONTROLLED COUPLING: Mouse sperm (examples indicated by arrows) swim through culture medium to reach egg cells.SKY FEUER, RINAUDO LAB


The paper
S.K. Feuer et al., “Sexually dimorphic effect of in vitro fertilization (IVF) on adult mouse fat and liver metabolomes,” Endocrinology, 155:4554-67, 2014.

The background
Embryos formed by in vitro fertilization (IVF) experience very different early conditions from naturally conceived embryos. In previous studies, Paolo Rinaudo of the University of California, San Francisco, and colleagues observed that IVF-conceived female mice were more insulin resistant and metabolized glucose poorly compared to normally conceived females, and that IVF mice of both sexes showed altered gene expression, which led them to wonder what might cause such lasting metabolic and transcriptional changes.

The experiments
Rinaudo’s team transferred IVF-conceived and normally conceived blastocysts into recipient mice. Two months later, when the animals were young adults, the researchers examined their liver, muscle, fat, and pancreatic tissues for metabolic parameters.

The result
Across tissues, the researchers observed many differences in metabolite levels between the IVF and natural cohorts, although they failed to find a distinctive “IVF fingerprint,” says Rinaudo. The normal sex disparities in fat metabolites shrank among the IVF mice, while in liver tissue the disparity was exaggerated. Fat tissue from IVF females also showed greater signs of oxidative stress. These alterations in metabolism and in underlying gene expression could play a role in the dysfunctional glucose metabolism and insulin resistance observed previously in mice, Rinaudo suspects.

The view ahead
The results suggest that the genome of IVF-conceived embryos “is utilized in a very different way, which translates into [their later] ability to handle metabolic changes,” says reproductive biologist Mark Green of the University of Melbourne in Australia. The big question, says Rinaudo, is “to discover if what happens in animals is true in human children.”

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January 26, 2015

We still have a lot to learn about the regulation of gene expression, don't we !?!

I haven't seen any "popular press" articles about genetic imprinting in a long long time. Any clues from work on imprinting that could be relevant to these observations?



Avatar of: Keith Loritz

Keith Loritz

Posts: 27

January 26, 2015

Cool article, but I did not see an answer to the question: Why would IVF yield a different phenotype compared to natural conception?

One place to check is obvious, culture media. As described under the image ". . . swim through culture medium to reach egg cells. . .". Is there too much glucose in the culture medium compared to fluids involved in natural fertilization?

Perhaps, given the results,  this is the better question to ask. Do offspring of mothers with exogenously induced poor glucose maintenance tend to themselves have poor glucose metabolism?


Avatar of: Alexandru


Posts: 89

January 26, 2015

Embryos formed by in vitro fertilization (IVF) experience very different early conditions from naturally conceived embryos.” (from article)


As a DNA wireless mirror, the mitochondria are returning data to the user and introduce the quantum physics to chemistry. The energetic balance and harmony for the body is wireless manipulated by maternal and paternal mitochondria. Because the offspring conceived by in vitro fertilization do not have paternal mitochondia the quantum biofeedback is different comparing with naturally conceived offspring and „what happens in animals is true in human children”.

Geneticists, please, read carefully:




and accept Adam mtDNA inheritance in addition to Eve mtDNA inheritance, because at the puberty the paternal mitochondrion is present only in the sperm of naturally offspring.

Thank you to The Scientist that gives me the permissions to bring hear my research results!

Avatar of: Sky Feuer

Sky Feuer

Posts: 1

Replied to a comment from Keith Loritz made on January 26, 2015

January 29, 2015

Hi Keith,

These are great questions and comments! An important thing to consider about the IVF culture environment is that although it is optimized for embryo development, it still doesn't fully recapitulate the female reproductive tract. The preimplantation embryo is normally exposed to a dynamic range of nutrients, pH, and oxygen tension between the points of fertilization and implantation, which support its ever-changing metabolic and growth needs. For example, glucose isn't the primary carbohydrate utilized in the earliest stages, but becomes very important as the embryo transitions from the oviduct to the uterus-- in conjunction with this, glucose concentrations in the oviductal fluid are lower than levels in the uterus. These variations in environment are generally not present in culture (although some groups perform a sequential culture, in which embryos are moved from one set of conditions to another). 

If you are interested in the effects of glucose, maternal diabetes, and hyperglycemia on oocytes and preimplantation development, Kelle Moley's group at Washington University, St. Louis has done some excellent work addressing these questions!

Avatar of: .....


Posts: 5

Replied to a comment from Keith Loritz made on January 26, 2015

January 31, 2015

EDIT: I see Sky provided an answer that addresses the composition of the media. Didn't read far enough. :)

Well, the researchers tested optimized media. The optimized media may well not be optimal, of course, and that could be an explanation. You'd have to look at papers describing how the optimized media was developed to get a sense of how close they think it is to natural settings. 

There are other possible explanations, though, such as the stress that implantation causes to the mother. Another is storage of sperm outside of optimal conditions (cold) before fertilization. Of course, these would be harder to fix in the process than changing the media. :)






Avatar of: Dulama R

Dulama R

Posts: 1

February 2, 2015

Evidence also suggests that the high doses of gonadotropin (FSH, hCG) administered for IVF can lead to aberrant DNA methylation and altered gene expression in the oocyte.

Avatar of: Hugh-F-61


Posts: 69

February 11, 2015

The cell's epigenetic status is reset sfter fertiluzation. The sperm DNA is massively demethylated (at least in mice) and methylation is not maintained in the oocyte DNA. There are epigenetically imprinted loci where the allele from the sperm is differently expressed compared to its homolog from the egg, and this differential expression may vary between tissues. Putting these two facts together and knowing that the environment can affect epigenetic signals, particularly DNA methylation, then if culture conditions have any affect on epigenetic programming,this sort of result is to be expected.

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