Persistence and intergenerational transmission of differentially expressed genes in the testes of intracytoplasmic sperm injection conceived mice

Abstract

Abstract:Intracytoplasmic sperm injection (ICSI) is commonly used to solve male infertility problems. Previous studies showed that early environmental exposure of an embryo may influence postnatal development. To detect whether ICSI operations affect the reproductive health of a male or his offspring, we established assisted reproductive technologies (ART) conceived mouse models, and analyzed gene expression profiles in the testes of both ICSI and naturally conceived (NC) newborn F 1 mice using micro-array analysis. Among the differentially expressed genes, we focused on the expression of eight male reproduction-related genes. Quantitative real-time reverse transcriptionpolymerase chain reaction (qRT-PCR) was used to analyze the expression of these genes in the testes of both adult and old F 1 generation mice and adult F 2 generation mice. Our results showed that down-regulated and somatic cell-expressed genes in newborn mice retained their differential expression patterns in adult and old F 1 generation individuals, implying the persistence and fetal origin of the alteration in the expression of these genes. The intergenerational transmission of differential gene expression was observed, but most changes tended to be reduced in adult F 2 generations. Controlled ovarian hyperstimulation (COH) and in vitro fertilization (IVF) mice models were added to explore the precise factors contributing to the differences in ICSI offspring. The data demonstrated that superovulation, in vitro culture, and mechanical stimulation involved in ICSI had a cumulative effect on the differential expression of these male reproductive genes.

Intracytoplasmic Sperm Injection Using DNA-Fragmented Sperm in Mice Negatively Affects Embryo-Derived Embryonic Stem Cells, Reduces the Fertility of Male Offspring and Induces Heritable Changes in Epialleles

“…When gene expression in the testes of both ICSI-produced and naturally conceived mice by micro-array analysis was examined, 474 (150 up-regulated and 324 down-regulated in ICSI mice) differentially expressed genes were identified representing several functional pathways, including those implicated in spermatogenesis, male meiosis I, spermatid development, gonad development and male genitalia development. It has been observed that such differential gene expression patterns are transmitted to the next generation [31] . It has been also reported that ICSI-derived mice exhibit a high level of spermatogenic cell apoptosis, suggesting a risk of the compromised fertility of male progeny [32] .…”

Long-term follow-up of children conceived through assisted reproductive technology

“…There is biological plausibility for such a concern because of the synchrony between ART procedures and crucial imprinting events. Moreover, in animal models, ART affects gene imprinting (Doherty et al, 2000;Khosla et al, 2001;Zaitseva et al, 2007;Li et al, 2011b;Wang N. et al, 2012;Wang L.Y., 2013), particularly for large offspring syndrome (LOF) in sheep and cattle, which is reminiscent of BWS in humans (Young et al, 1998). However, some studies have suggested that the subfertile condition of the parents may also be responsible for imprinting disorders Ludwig et al, 2005).…”

Heterochronic bilateral ectopic pregnancy after ovulation induction

“…At the first exploration, the contralateral implanted embryo was too underdeveloped to be spotted by laparoscopy, which contributed to the consequently delayed diagnosis of ectopic pregnancy. IVF or intracytoplasmic sperm injection (ICSI) following ovulation induction has shown adverse effect on offspring, and this study showed the association of ovulation with bilateral ectopic pregnancy (Wang et al, 2013;Xing et al, 2014).…”