Maternal undernutrition induces premature reproductive senescence in adult female rat offspring

An adverse uterine nutritional environment during pregnancy results in premature reproductive senescence in adult rats.

Omid Khorram, M.D., Ph.D., Erin Keen-Rinehart, Ph.D., Tsai-Der Chuang, Ph.D., Michael G. Ross, M.D., Mina Desai, Ph.D.

Volume 103, Issue 1, Pages 291-299


To determine the effects of maternal undernutrition (MUN) on the reproductive axis of aging offspring.

Animal (rat) study.

Research laboratory.

Female Sprague-Dawley rats.

Food restriction during the second half of pregnancy in rats.

Main Outcome Measure(s):
Circulating gonadotropins, antimüllerian hormone (AMH), ovarian morphology, estrous cyclicity, and gene expression studies in the hypothalamus and ovary in 1-day-old (P1) and aging adult offspring.

Offspring of MUN dams had low birth weight (LBW) and by adult age developed obesity. In addition, 80% of adult LBW offspring had disruption of estrous cycle by 8 months of age, with the majority of animals in persistent estrous. Ovarian morphology was consistent with acyclicity, with ovaries exhibiting large cystic structures and reduced corpora lutea. There was an elevation in circulating T, increased ovarian expression of enzymes involved in androgen synthesis, an increase in plasma LH/FSH levels, a reduction in E2 levels, and no changes in AMH in adult LBW offspring compared with in control offspring. Hypothalamic expression of leptin receptor (ObRb), estrogen receptor-α (ER-α), and GnRH protein was altered in an age-dependent manner with increased ObRb and ER-α expression in P1 LBW hypothalami and a reversal of this expression pattern in adult LBW hypothalami.

Our data indicate that the maternal nutritional environment programs the reproductive potential of the offspring through alteration of the hypothalamic-pituitary-gonadal axis. The premature reproductive senescence in LBW offspring could be secondary to the development of obesity and hyperleptinemia in these animals in adult life.

  • Shvetha Zarek

    This is an experimental murine model study that evaluated the effect of maternal undernutrition (MUN) on the reproductive potential of adult female rat offspring. The authors have a well characterized animal model of fetal programming utilizing Sprague Dawley rats where the animals underwent 50% food restriction for the second half of gestation. Experiments involved estrous cycle monitoring, histology assessment of hypothalamic and ovarian tissue, plasma hormone assessment and protein quantification of GnRH, leptin receptor (ObRb) and Estrogen receptor-α of the hypothalamic and ovarian tissue. The pups of MUN dams demonstrated lower birth weights and decreased plasma leptin levels at day of life 1 but when nursed by healthy control dams, underwent a rapid increase in weight, body fat and plasma leptin levels and insulin. The LBW adult female offspring (n=5) demonstrated significant increases in LH, FSH and testosterone but lower estradiol levels compared to controls (n=8) in the same phase of the cycle with no difference in AMH. Estrous cyclicity was disrupted with only 20% of LBW offspring with normal cyclical function and a significant percentage of LBW females in persistent estrous. LBW females demonstrated a significant decrement in hypothalamic protein expression of GnRH and an increase in leptin and estrogen receptor compared to controls on day of life one. By 10 months, this pattern had reversed. Ovarian morphology of LBW adult female rats was consistent with acyclicity and anovulation.

    This is an interesting study on the fertility and premature reproductive aging of the female offspring of MUN dams. Do the authors plan to continue to monitor and report the effects in the F2 generation (mating the MUN restricted offspring that were given an ad libitum diet)? This may be more difficult given the reported reduction in fertility and estrous cyclicity but it would be interesting to see the effects of MUN on the F2 generation. There was a recent publication in Science that demonstrated metabolic phenotypic aberrations in F2 adult male offspring (mice model) even when the F1 generation (born from undernourished dams) did not experience postnatal nutritional changes (DOI 10.1126/science.1255903). Thank you very much for an interesting experimental study on maternal undernutrition!

    • Omid Khorram

      Thank you for your comment. Looking at f2 is of interest to us but unfortunately we do not have the funding for this expensive experiment

      • Shvetha Zarek

        Thank you for your reply. That is unfortunate that there is a lack of funding to evaluate the F2 generation. Kudos to you and co-authors for a fascinating study!

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