Research Centre for Reproductive Health , Discipline of Obstetrics and Gynaecology, Level 3 Medical School South, Robinson Institute, University of Adelaide, Adelaide, South Australia 5005, Australia.
Hum Reprod. 2012 May;27(5):1391-400. doi: 10.1093/humrep/des030. Epub 2012 Feb 21.
Obesity and related conditions, notably subfertility, are increasingly prevalent. Paternal influences are known to influence offspring health outcome, but the impact of paternal obesity and subfertility on the reproductive health of subsequent generations has been overlooked.
A high-fat diet (HFD) was used to induce obesity but not diabetes in male C57Bl6 mice, which were subsequently mated to normal-weight females. First-generation offspring were raised on a control diet and their gametes were investigated for signs of subfertility. Second-generation offspring were generated from both first generation sexes and their gametes were similarly assessed.
We demonstrate a HFD-induced paternal initiation of subfertility in both male and female offspring of two generations of mice. Furthermore, we have shown that diminished reproductive and gamete functions are transmitted through the first generation paternal line to both sexes of the second generation and via the first generation maternal line to second-generation males. Our previous findings that founder male obesity alters the epigenome of sperm, could provide a basis for the developmental programming of subfertility in subsequent generations.
This is the first observation of paternal transmission of diminished reproductive health to future generations and could have significant implications for the transgenerational amplification of subfertility observed worldwide in humans.
肥胖症及相关病症（尤其是不孕）的发病率日益升高。已知父系因素会影响后代的健康结果，但父系肥胖症和不孕对后代生殖健康的影响却被忽视了。
我们用高脂肪饮食（HFD）使雄性 C57Bl6 小鼠肥胖，但不诱发糖尿病，然后让它们与体重正常的雌性小鼠交配。第一代后代在正常饮食下成长，我们检测了它们的配子是否有不孕的迹象。然后我们从第一代的雌雄两性中产生第二代后代，并对它们的配子进行类似的评估。
我们在两代小鼠的雄性和雌性后代中都发现了 HFD 引起的父系不孕现象。此外，我们还表明，第一代雄性的生殖和配子功能的下降会通过父系遗传到第二代的雌雄两性，也会通过母系遗传到第二代的雄性。我们之前的研究发现，创始雄性肥胖会改变精子的表观基因组，这可能为后代不孕的发育编程提供了基础。
这是首次观察到父系将生殖健康下降遗传给后代的现象，这可能对全球人类中观察到的不孕的跨代放大具有重要意义。
