Human reproductive success tied to mitochondrial organization in eggs

December 19, 2000

The viability of a developing human embryo appears to be related to the clustering and subsequent symmetrical distribution of tiny DNA structures in the egg's fluid surrounding its nucleus prior to the first cell division, according to a new Colorado study.

University of Colorado at Boulder biology Professor Jonathan Van Blerkom said the study showed the roughly 140,000 tiny DNA structures, or mitochondria, in each egg are controlled by arrays of tube-like structures. The microtubules are created and the mitochonria migrate along them in the first few hours after fertilization.

A paper on the subject by Van Blerkom, CU-Boulder researcher, with Colorado Reproductive Endocrinology researcher Patrick Davis and Colorado Reproductive Endocrinology infertility specialist Dr. Sam Alexander, appeared in the December issue of the prestigious monthly journal Human Reproduction.

"I believe the take-home message is that these findings may help us determine the embryo quality at an earlier stage," said Dr. Alexander. "We feel that using methods to judge embryo quality in the first three days of culture is a much more sensible and intelligent approach than the five-day, survival of the fittest, embryo approach."

"Being able to determine the association between mitochondrial organization and egg competence non-invasively at an earlier stage would be a large step in predicting the eventual success or failure of the developing embryo," said Van Blerkom.

If the microtubule arrays in the egg cell do not mirror each other at the initial cell division, half of the dividing cells, or blastomeres, may carry too few mitochondria. Mitochondria are passed on maternally to offspring and are responsible for certain inherited traits and energy production, Van Blerkom said.

The research emphasis at the CRE clinic at Rose Medical Center has recently focused on genetics and blood flow into the follicles. "The follicles have provided us with more information the past few years, allowing us to make better decisions regarding egg selection for the in-vitro process," Alexander said.

"If asymmetry is the case, the blastomeres may have a reduced competency and be inadequate to support normal cellular function as the cells continue to divide," said VanBlerkom, also a partner at Colorado Reproductive Endocrinology, a private in-vitro fertilization clinic at Denver's Rose Medical Center. "Eventually there may not be enough mitochondria in the blastomeres to produce a healthy embryo."

The researchers stained individual mitochondria in fertilized eggs obtained from donors with a fluorescent orange dye and followed their movements and associated cell division in petri dishes for up to five days using scanning laser microscopes. The new findings may help explain the failures of seemingly healthy fertilized human eggs during in-vitro fertilization.

The Colorado team believes in-vitro fertilization research should focus more on the eggs while they still are encased in the ovarian follicles. "Each follicle is surrounded by tiny blood vessels that give it a unique biology and seems to be associated with its viability, competence and ultimate fate," Van Blerkom said.

Even embryos exhibiting asymmetrical distribution of their mitochondria -- which are fairly common events -- can develop into normal fetuses unless the distribution of mitochondria is severely asymmetrical, Van Blerkom said. The researchers document each cell division in developing eggs with powerful microscopes in order to help them select the most viable embryos for implantation.

Studies have shown fertilization and egg implantation success is higher if the blood flow through the tiny follicle vessels to the egg is strong and steady. CRE researchers use ultrasound to conduct "Pulse Doppler" tests in order to measure the blood flow and visually examine the tiny blood vessels to check their competency.

Egg selection is crucial because the sperm may just be following a script that already has been written in the jelly-like fluid surrounding the nucleus, known as cytoplasm, in the egg, Van Blerkom said.

The microtubules originate from cell material contained in both the unfertilized egg and the sperm, Van Blerkom said. Once the sperm enters the egg, the microtubule arrays began to form and the mitochondria began traveling along these pathways.

Van Blerkom said the symmetry or asymmetry of the mitochondria-carrying microtubules may even be programmed in the genetic "script" of the egg prior to fertilization. "Whether the embryo is going to work or not may be determined well before ovulation even takes place."
Additional contacts:
Sam Alexander, (303) 321-7115
Jim Scott, (303) 492-3114

University of Colorado at Boulder

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