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Sexual Dimorphism in Susceptibility to Age-Dependent Metabolic Disorders in Mice Born through ICSI
Cell and Molecular Biology
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Intracytoplasmic sperm injection (ICSI), as an assisted reproductive technology (ART), has been increasingly used in human fertility clinics to treat male infertility and achieve pregnancy. Consequently, the majority of the so-called “test-tube babies” are born through ICSI nowadays. Many studies have shown that epigenetic alterations could occur in early embryos, which are largely due to extensive in vitro manipulation (e.g., washing, culture, injection, etc.) and/or superovulation protocol used for oocyte collection. Given that epigenetic alterations may not necessarily cause lethality, it is not surprising that the ICSI babies are mostly born “healthy”. However, the long-term potential adverse effects of ICSI-based ART on the health perspectives of these individuals have not been reported because of the relatively short history of ART application in humans (~40 years). We tackled this important question using mice (CD-1 strain) by examining metabolic profiles (e.g., GTT: glucose tolerance test and ITT: Insulin tolerance test) and the lifespan of mice derived from ICSI in comparison to those from natural conception (NC). Our results revealed a sex-, and age-dependent predisposition of metabolic disorders. While ICSI males displayed insulin insensitivity at 3 and 10 months of age, ICSI females showed both impaired glucose tolerance and insulin insensitivity at the same two timepoints. Interestingly, both sexes showed normal GTT and ITT results at the age of 6 months. Moreover, The overall body weight of ICSI mice was greater than that of the NC controls in both sexes, and the body weight of ICSI females was generally higher than that of the NC females at the age of 2-3 months, 10 months and older. When fed with high-fat diet (60% fat contents) for three months, ICSI females were more susceptible to developing metabolic disorder than NC females, as characterized by greater weight gain and aberrant ITT results. Moreover, the lifespan of the ICSI males appeared to be shorter than that of NC males, whereas ICSI females displayed a normal lifespan. Our data suggest that female mice born through ICSI are more susceptible, in general, to metabolic disorders than male mice, but they tend to outlive the ICSI male mice.