Maternal undernutrition induces premature reproductive senescence in adult female rat offspring

Abstract

Objective To determine the effects of maternal undernutrition (MUN) on the reproductive axis of aging offspring. Design Animal (rat) study. Setting Research Laboratory. Animals Female Sprague-Dawley rats. Intervention(s) Food restriction during the second half of pregnancy in rats. Main Outcome Measures Circulating gonadotropins, Anti-Mullerian Hormone (AMH), ovarian morphology, estrous cyclicity and gene expression studies in the hypothalamus and ovary in 1 day old (P1) and aging adult offspring. Results Offspring of MUN dams had low birth weight (LBW) and by adult age developed obesity. 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 testosterone (T), increased ovarian expression of enzymes involved in androgen synthesis, an increase in plasma Leuteinizing (LH/)/Follicle Stimulating hormone (FSH) levels, reduced estradiol (E2) levels and no changes in AMH in adult LBW offspring compared to control offspring. Hypothalamic expression of leptin receptor (OBRb), estrogen receptor-α (ER-α) and Gonadotropin Releasing hormone (GnRH) protein were altered in an age-dependent manner with increased ObRb, ER-α expression in P1 LBW hypothalami and a reversal of this expression pattern in adult LBW hypothalami. Conclusion Our data indicates that the maternal nutritional environment programs reproductive potential of the offspring through alteration of the hypothalamic-pituitary-gonadal axis. The premature reproductive senescence in LBW offspring could be secondary to development of obesity and hyperleptinemia in these animals in adult life.

The impact of adipose tissue-derived factors on the hypothalamic-pituitary-gonadal (HPG) axis

“…33 It is of particular interest that maternal malnutrition additionally appears to affect the fertility of female offspring, leading to premature reproductive senescence. 34 During the menstrual cycle leptin levels vary, the highest appearing in the luteal phase and the lowest during the early follicular phase. 35 Leptin levels positively correlate with FSH and LH.…”

Gender differences in developmental programming of cardiovascular diseases

“…Experimental studies also implicate a role for sex steroids and involvement of the RAS, the renal nerves, endothelin and oxidative stress in the etiology of BP regulation following a developmental insult (Figures 3 and 4). Recent studies indicate that maternal undernutrition in the rat programs early reproductive senescence [108–109] (Figure 4). Whether this is linked to loss of protection against CV risk is not yet known.…”

Fetal undernutrition is associated with perinatal sex-dependent alterations in oxidative status

“…To assess our hypothesis we have studied a rat model of IUGR induced by maternal undernutrition during the second half of gestation (MUN), which has been previously demonstrated to program for hypertension and obesity in adult age [5,[21][22][23][24]. In male and female offspring from MUN and Control dams, we have assessed individual plasma biomarkers of oxidative damage and antioxidant capacity and calculated a global score (oxy-score) from them.…”