Letter by Andreassi Regarding Article, “Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies”
To the Editor:
In a recent issue of Circulation, the elegant manuscript by Scherrer et al1 reported a marked vascular dysfunction of the systemic and pulmonary circulation in healthy children and adolescents conceived by using assisted reproductive technologies (ARTs). As mentioned in the article, epigenetic mechanisms may play a key role in regulating gene expression at the vascular level. Epigenetics refers to modifications (DNA methylation and specific histone tail post-translational modifications) of the genome without change in primary DNA sequence, that can be inherited both mitotically and meiotically. Although results from animal studies indicate that ARTs are associated with epigenetic alternations, data in humans are inconsistent and great caution is recommended in extrapolating these findings to humans.2 Furthermore, a very recent study did not find evidence of aberrant methylation on a genome-wide level as well as no differences in percentage of methylation of 8 candidate genes.3 These results corroborate an earlier study that found no increase of epigenetic abnormalities in a cohort of 5891 neonates conceived by intracytoplasmic sperm injection.3 Therefore, it still remains unclear whether more subtle changes in DNA methylation occur commonly, leading to differences in gene expression and clinical phenotypes in ART children.3 On the other hand, much evidence supports the possibility that DNA damage in a gamete (oocytes and sperm cells) or in an embryo, to the different phases of an ART treatment (eg, fertility drugs, in vitro culture), may impact the embryo development or have long-lasting developmental consequences. For instance, ovarian stimulation in ART treatments induces the development and growth of multiple follicles, resulting in high numbers of oocytes associated with an increased chromosomal DNA error rate, especially in women aged ≤40 years. In addition, the integrity of sperm DNA is of crucial importance in the clinic use for ART.4 Only those spermatozoa with normal morphology, motility, and normal sperm DNA damage are selected and considered to be good sperm cells for clinical use. Such sperm parameters, however, do not ensure for a total DNA integrity. Spermatozoa with highly damaged DNA may have a negative impact on the health of the offspring later in life, as animal studies have shown that spermatozoa DNA-fragmented spermatozoa can transmit genetic defects leading to a long-term manifestation of a variety of deleterious phenotypes, such as aberrant growth, premature aging, abnormal behavior, and tumors.4 Of particular relevance for vascular dysfunction may be the DNA damage associated with critically shortened telomeres in germ cells. Research carried out over the last 10 years has demonstrated the relevance of shortened telomeres in vascular disorders and cardiac events. In fact, an activated DNA response pathway induced by both oxidative DNA damage and telomere dysfunction is believed to be the crucial mediator for increased premature vascular aging or apoptosis, playing a pathogenetic role in atherosclerosis.5
Additional research is thus needed to define causal pathways between ART-related health problems and both prenatal epigenetic and genetic alterations, and their possible relevance to subtle cardiovascular consequences reported in ART offspring.
The study by Scherrer et al1 highlights the importance of elucidating the molecular and cellular mechanisms that contribute to increase all potential cardiovascular risks associated with the use of reproductive technology.
Maria Grazia Andreassi MSc, PhD
CNR, Institute of Clinical Physiology
- © 2013 American Heart Association, Inc.