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BACKGROUND: In vitro fertilization has transformed reproductive medicine, yet offspring conceived through in vitro fertilization display elevated risks for diverse long-term health conditions, with underlying mechanisms unclear. Long Interspersed Nuclear Elements-1, a mobile genetic element responsive to environmental stress, represents a potential mediator. OBJECTIVE: This study aimed to test the hypothesis that in vitro fertilization procedures may act as an embryonic stressor that alters Long Interspersed Nuclear Elements-1 dynamics, potentially contributing to genomic instability associated with long-term disease susceptibility. STUDY DESIGN: Umbilical cord blood or peripheral blood from 33 in vitro fertilization and 42 naturally conceived neonates were collected for whole-genome sequencing. Total Long Interspersed Nuclear Elements-1 proportion in individual genome was counted with Bowtie2 software. De novo Long Interspersed Nuclear Elements-1 insertion and Long Interspersed Nuclear Elements-1 deletion were detected with Mobile Element Locator Tool. Three parent-matched in vitro fertilization-naturally conceived sibling pairs were included to control for genetic background. Disease association analysis was performed for genes within 500 kb of differential Long Interspersed Nuclear Elements-1 sites in The Database for Annotation, Visualization and Integrated Discovery (DAVID). Statistical analysis was performed using the R language. RESULTS: In vitro fertilization offspring demonstrate elevated global Long Interspersed Nuclear Elements-1 content compared to naturally conceived controls (P=.04). This finding was corroborated in 3 sibling pairs from identical genetic backgrounds, where in vitro fertilization-conceived children consistently exhibited higher Long Interspersed Nuclear Elements-1 levels than their naturally conceived siblings. Eleven genomic loci with differential Long Interspersed Nuclear Elements-1 insertion frequencies and 14 loci with differential Long Interspersed Nuclear Elements-1 deletion frequencies between in vitro fertilization offspring and naturally conceived controls were identified. Notably, these differential Long Interspersed Nuclear Elements-1 sites demonstrated significant enrichment near genes implicated in metabolic, cardiovascular, neuropsychiatric, and neoplastic diseases, conditions associated with in vitro fertilization conception. CONCLUSION: These findings provide preliminary evidence that in vitro fertilization conception is associated with increased Long Interspersed Nuclear Elements-1 content and altered genomic distribution of Long Interspersed Nuclear Elements-1 elements. The proximity of these differential Long Interspersed Nuclear Elements-1 sites to disease-associated genes suggests a plausible genomic mechanism linking in vitro fertilization-associated embryonic stress to elevated disease risk. This work provides valuable molecular insights that may inform the ongoing discussion about assisted reproductive technology safety and suggests that continued attention to genomic integrity in in vitro fertilization-conceived individuals would be beneficial.
An in vitro fertilization assay employing zona-free hamster eggs was used to analyze human spermatozoal fertilizing ability. Human spermatozoa were preincubated for 18 to 20 hours in Biggers, Whitten, and Whittingham's medium (1971) at a concentration of 1 X 10(7) sperm/ml prior to the addition of zona-free superovulated hamster eggs. Eggs were examined microscopically 2 hours later for evidence of swelling or decondensing sperm heads in the cytoplasm. A total of 6266 eggs were examined in assays for both suspected fertile and infertile donors; 50 eggs/sample were examined. The percentage fertilization was found to range from 14% to 100% in the suspected fertile group with an average of 56.3%. The sperm concentration in this fertile group ranged from 22 to 303 million/ml with an average of 114. The suspected infertile samples yielded fertilization rates of 10% or less and an average count of 50.6 million/ml. These data suggest that human spermatozoa fuse with the vitelline membrane of zona-free hamster eggs and decondense with varying efficiencies. The percentage of fertilization in this cross-species system did not show a significant correlation with sperm concentration or motility. However, suspected infertile samples always yielded 10% or less fertilization in this assay. This method may have potential value as a diagnostic tool in evaluating human spermatozoal fertilizing capacity which avoids the ethical and logistcal problems associated with fertilization of human eggs in vitro.
The following recommendations and conclusions are based upon results of fertility and laboratory studies, and general trends from field investigations. Fertility results due to the addition of enzymes have been variable and contradictory. Flushing of ampules with dry, gaseous nitrogen prior to filling has become a routine practice in processing semen to be frozen. For control of Vibrio fetus and Leptospira pomona, 2,000 micrograms of streptomycin and 1,000 u polymyxin B sulfate should be added per milliliter of raw semen immediately after collection. The extender for initial dilution should contain the same concentration of antibiotics used for raw semen plus 500 u penicillin. The glycerol portion of the extender should contain 500 u penicillin per milliliter. The effect of addition of sugars on fertility has been highly variable. The primary beneficial effect is probably due to their cryoprotective properties. A myriad of concoctions have been added to bovine semen and the results have been highly variable with respect to both motility and fertility. Results of subsequent experiments have rarely proven that addition of exotic compounds or mixtures has been of value. Higher mean fertility was obtained with semen in straws in 14 of 21 comparisons with ampules. The differences in favor of straws ranged from 1.1 to 18.9; while the range in favor of ampules was .1 to 4.4 percentage points. Fertility obtained with pellets has ranged from minus 12.8 to plus 11.9 percentage points in nonreturn rate (NR), compared to the corresponding NR with semen in ampules. Fertility of semen in ampules was higher in five of eight studies. Fertility of pelleted semen has ranged from minus 9.5 to plus 6.0 percentage points compared with straws. Fertility was higher for semen in pellets in only one of five investigations. Pellets should not be used until the potential for pathogenic contamination and exchange of spermatozoa among pellets is eliminated. There is a potential for higher fertility with semen in straws as compared to other packaging systems, but the issue of liquid nitrogen (LN) entry and possible contamination of semen should be further investigated. In general, fertility obtained with semen frozen in the .25 ml straw has been equal to or higher than semen in larger packages. However, they cannot be unequivocally recommended due to other considerations. From laboratory studies, it appears that greater spermatozoan survival is obtained when semen frozen in straws is thawed in water at 35 C or above.(ABSTRACT TRUNCATED AT 400 WORDS)