Genomic Imprinting in Disruptive Spermatogensis

Abstract & Commentary

Synopsis: Oligoasthenospermia (male factor infertility) is associated with abnormal genomic imprinting of the sperm, a feature that may predispose to abnormal embryogenesis, including a risk of rare developmental abnormalities and cancer in adulthood, if fertilization occurs, as it may because of the availability of assisted reproductive techniques.

Source: Marques CJ, et al. Lancet. 2004;363: 1700-1702.

It is commonplace to suspect that technological breakthroughs are not without risks. Although assisted reproductive technologies have aided many couples in their quest to become parents, there has always been a concern about the potential risks. The present article reveals one of the mechanisms that may result in abnormal, but nonlethal, embryogenesis. Genomic imprinting is a nonrandom event by which either the paternal or maternal allele is "silenced" after fertilization. Silencing is necessary to control gene dosage. Genomic silencing is not random and the gene to be silenced depends on the sex of embryo. Sometimes the maternal allele is silenced and sometimes the paternal allele. Assisted reproductive technologies have been associated with a rise in syndromes that are thought to represent abnormal genomic imprinting, including Angelman’s syndrome and Beckwith-Wiedeman’s syndrome. It has been suggested that the methods by which embryos are cultured in the laboratory are responsible for abnormal gene silencing. In the present study, Marques and colleagues tested the hypothesis that, at least in some instances, abnormal male gametes may confer abnormal genomic imprinting.

To test the hypothesis that abnormal sperm may harbor abnormal genomic imprinting, Marques et al looked at methylation pattens of the DNA of sperm of men undergoing assisted reproduction. Methylation of cytosine in CpG islands is the main mechanism by which genes are silenced. The methylation patterns are erased in embryonic germ cells and then reset during gametogenesis or after fertilization. Marques et al examined methylation patterns in spermatozoan DNA from semen samples from 123 normozoospermic and oligozoospermic men undergoing routine semen analysis for infertility diagnosis. The maternal imprint was correctly erased in all normozoospermic and oliogzoospermic samples. Paternal imprinting was normal in all men with a normal semen analysis (> 20 million sperm/mL with normal motion and morphology), but abnormal in 24% of men with oligozoospermia. In men with mild oligospermia, the rate of abnormal paternal methylation was 17%, and in men with severe oligospermia, it was 30%.

Comment by Sarah L. Berga, MD

There is no sense shutting one’s eyes to the downsides of technology. One intuitively senses that tampering with mother nature cuts both ways. To tamper, I believe, is an inherent human legacy and we have been at it forever. It is arguably better, I fear, to understand the trade-offs so that one can counsel appropriately than it is to glibly assume that there are no risks. The benefit of knowing, however, is not to proscribe, but rather to enlighten those who must choose. Life and life-assisting technologies have both known and hidden risks. Failure to conceive is devastating and has profound psychological implications. Thus, it is no wonder that couples seek remedies. To the extent that we can, we must describe the pros and cons. If the individuals faced with such decisions understood some of the risks, would they choose differently? It is difficult to know what one would do unless one was faced with the decision.

The results of the present study suggest that abnormal sperm may give rise to abnormal offspring because of abnormal genomic imprinting in the sperm. While this may seem surprising, it is important to recognize that this is an inherent risk and not one that is likely to go away merely by improving embryo culture methodologies. Perhaps it will be something that we can learn to screen for, either in the sperm or in the embryos.

The present study is not definitive. The study does not prove that the abnormal methylation patterns in sperm were capable of being transmitted to embryos. Perhaps embryos with abnormal paternal imprinting do not do well in the laboratory and are unlikely to be transferred. Perhaps embryos that result from sperm with abnormal genomic imprinting do not implant with great success. It is important to remember that even technological advances carry built-in safeguards.

Sarah L. Berga, MD, James Robert McCord Professor and Chair, Department of Gynecology and Obstetrics, Emory University School of Medicine, is Associate Editor for OB/GYN Clinical Alert..