Advancement in reproductive senescence induced by neonatal hypoxia-ischemia in rats.

EZQUER, M.,; BUZZIO, O.L.; SELTZER, A.,; JAHN, G.A.

Vancouver, Canada

Congreso; XXXVII Annual Meeting of the Society for the Study of Reproduction.; 2004

Society for the Study of Reproduction

Perinatal hypoxia-ischemia is the single most important cause of brain injury in the newborn, and has potentially devastating and lifelong consequences. There are very few studies on the impact of perinatal hypoxic states on the future reproductive performance. In the present study we explored the effects of cerebral hypoxia-ischemia (HI) (or hypoxia alone, H) on reproductive aspects in the female rat. Seven-day-old neonatal female rats underwent permanent unilateral carotid ligation followed by an hypoxic episode (6.5%O2 for 40 min.) or hypoxia alone. In this model the pattern of brain injury resembles that of hypoxic ischemic injury in term human infants. The expression (relative to b-actin) of markers of inflammation like: iNOS, nNOS, TNFa; growth factors: IGF-1, IGF-1BP3, IGF-1BP5 and receptors: estrogen a and b and m-opioid was measured by RT-PCR in RNA from mediobasal hypothalamus, 48hs after the injury. The date of vaginal opening was determined and thereafter cyclicity was checked by vaginal smears. Determination of the hormonal profile by RIA was performed at 3 (rats showing regular 4 day estrous cycles) and 7 months of age. Results: The infant HI and H rats showed a decrease in the expression of nNOS: Control (C) 1.205 ± 0.095 H 0.773 ± 0.133 HI 0.527 ± 0.07; iNOS: C 0.854 ± 0.059 HI 0.212 ± 0.086; IGF-1 C 1.547 ± 0.143 HI 0.758 ± 0.111; bER C 0.513 ± 0.052 H 0.316 ± 0.033 HI 0.171 ± 0.029; m opioid receptor C 0.483 ± 0.051 H 0.208 ± 0.036 HI 0.222 ± 0.038 and increases in BP-3 C 0.643 ± 0.040 HI 0.877 ± 0.061 and BP-5 C 1.04 ± 0.02 H 1.33 ± 0.03 HI 1.26 ± 0.07. These changes were totally or partially antagonized by the previous administration of a-tocopherol (free radical scavenger). We did not find differences in growth profiles, onset of puberty, pregnancy rates, number of pups or efficiency of lactation. The proestrous LH surge was significantly decreased in HI (60%) and H (80%) rats at 3 months. The HI and H rats started to show prolonged estrous phases at 5-6 months of age, two to three months earlier than controls. Conclusions: the hipoxic-ischemic injury produced an advance in reproductive senescence associated with an early decrease in the LH preovulatory surge which may presumably be consequence of the observed alterations in mediobasal hypothalamus gene expression, that may be mediated at least in part by the production of free radicals.