Large offspring syndrome

Abstract

Beckwith-Wiedemann syndrome (BWS) is a human loss-of-imprinting syndrome primarily characterized by macrosomia, macroglossia, and abdominal wall defects. BWS has been associated with misregulation of two clusters of imprinted genes. Children conceived with the use of assisted reproductive technologies (ART) appear to have an increased incidence of BWS. As in humans, ART can also induce a similar overgrowth syndrome in ruminants which is referred to as large offspring syndrome (LOS). The main goal of our study is to determine if LOS shows similar loss-of-imprinting at loci known to be misregulated in BWS. To test this, Bos taurus indicus × Bos taurus taurus F1 hybrids were generated by artificial insemination (AI; control) or by ART. Seven of the 27 conceptuses in the ART group were in the > 97th percentile body weight when compared with controls. Further, other characteristics reported in BWS were observed in the ART group, such as large tongue, umbilical hernia, and ear malformations. KCNQ1OT1 (the most-often misregulated imprinted gene in BWS) was biallelically-expressed in various organs in two out of seven overgrown conceptuses from the ART group, but shows monoallelic expression in all tissues of the AI conceptuses. Furthermore, biallelic expression of KCNQ1OT1 is associated with loss of methylation at the KvDMR1 on the maternal allele and with downregulation of the maternally-expressed gene CDKN1C. In conclusion, our results show phenotypic and epigenetic similarities between LOS and BWS, and we propose the use of LOS as an animal model to investigate the etiology of BWS.

Downregulation of Long Non-Coding RNA Kcnq1ot1: An Important Mechanism of Arsenic Trioxide-Induced Long QT Syndrome

“…Fortunately, Kcnq1ot1 is a relatively conserved lncRNA and likely exerts similar effects in different species. For instance, the dysfunction of Kcnq1ot1 is responsible to Beckwith-Wiedemann syndrome in humans, similar to what has been observed for large offspring syndrome in bovines [34, 35]. In the present study, we found that the aberrant expression of lncRNA Kcnq1ot1 was involved in ATO-induced LQTS in mice and could likely have a similar effect in humans.…”

Exposure of bovine oocytes and embryos to elevated non-esterified fatty acid concentrations: integration of epigenetic and transcriptomic signatures in resultant blastocysts

“…Jungheim et al [26] showed that mouse embryos, exposed to elevated palmitic acid concentrations, presented an altered embryonic metabolism and development, with lasting adverse effects on growth patterns in offspring suggested to be associated with aberrant epigenetic programming. Assisted reproduction techniques have also been shown to influence epigenetic mechanisms during oocyte maturation and preimplantation embryo culture, leading to, for example, large offspring syndrome in ruminants [27] or a higher risk for metabolic syndrome in children born after in vitro fertilisation [28, 29]. …”

Sex and the preimplantation embryo: implications of sexual dimorphism in the preimplantation period for maternal programming of embryonic development

“…Thus, developmental programming during this time is inherent in the embryo and not the result of alteration in maternal function later in pregnancy. Among the changes in the preimplantation embryo that are likely responsible for modifications of postnatal phenotype are alterations in gene expression (Kwong et al 2006; Gad et al 2012; Calle et al 2012), the epigenome (Lucas, 2013; Chen et al 2013; Urrego et al 2014; Sun et al 2015) and patterns of embryonic growth and differentiation (Kwong et al 2000; Eckert et al 2012; Bromfield et al 2014). Such changes may be particularly profound during the preimplantation period because it is at this time that the basic patterns of development are being established, including re-establishment of DNA methylation marks (Rivera and Ross, 2013) and formation of the first differentiated cell lineages from which subsequent organs and tissues are derived.…”

“…In addition, alterations in developmental processes caused by embryo culture (Watkins et al 2007; Farin et al 2010; Chen et al, 2013; Sampino et al 2014) could reflect, at least in part, the absence of critical maternal regulatory molecules or, for the case of addition of serum to culture medium (Fernández-Gonzalez et al 2004; Calle et al 2012; Serrano et al 2014), alteration of embryonic function by bioactive molecules not normally involved in control of development. In addition to embryokines, developmental programming in utero or in culture could involve changes in cellular energy metabolism in the developing embryo.…”