Inhibition of 5alpha-reductase activity in late pregnancy decreases gestational length and fecundity and impairs object memory and central progestogen milieu of juvenile rat offspring

Jason J. Paris, Paula J. Brunton, John A. Russell, Alicia A. Walf, Cheryl A. Frye

Research output: Contribution to journalArticlepeer-review

Abstract

Psychological, physical, and/or immune stressors during pregnancy are associated with negative birth outcomes, such as preterm birth and developmental abnormalities. In rodents, prenatal stressors can alter the expression of 5alpha-reductase enzymes in the brain and may influence cognitive function and anxiety-type behaviour in the offspring. Progesterone plays a critical role in maintaining gestation. Here it was hypothesised that 5alpha-reduced progesterone metabolites influence birth outcomes and/or the cognitive and neuroendocrine function of the offspring. 5alpha-reduced steroids were manipulated in pregnant Long-Evans rats via administration of vehicle, the 5alpha-reduced, neuroactive metabolite of progesterone, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP, allopregnanolone; 10 mg/kg/ml, SC), or the 5alpha-reductase inhibitor, finasteride (50 mg/kg/ml, SC), daily from gestational days 17-21. Compared to vehicle or 3alpha,5alpha-THP treatment, finasteride, significantly reduced the length of gestation and the number of pups per litter found in the dams' nests after parturition. The behaviour of the offspring in hippocampus-dependent tasks (object recognition, open field) was examined on post-natal days 28-30. Compared to vehicle-exposed controls, prenatal 3alpha,5alpha-THP treatment significantly increased motor behaviour in females compared to males, decreased progesterone content in the medial prefrontal cortex (mPFC) and diencephalon, increased 3alpha,5alpha-THP and 17beta-estradiol content in the hippocampus, mPFC, and diencephalon, and significantly increased serum corticosterone concentrations in males and females. Prenatal finasteride treatment significantly reduced object recognition, decreased hippocampal 3alpha,5alpha-THP content, increased progesterone concentration in the mPFC and diencephalon, and increased serum corticosterone concentration in female (but not male) juvenile offspring, compared with vehicle-exposed controls. Thus, inhibiting formation of 5alpha-reduced steroids during late gestation in rats reduces gestational length, the number of viable pups/litter, and impairs cognitive and neuroendocrine function in the juvenile offspring.
Original languageUndefined/Unknown
Pages (from-to)1079-1090
JournalJournal of Neuroendocrinology
Volume23
Issue number11
Early online date15 Sep 2011
DOIs
Publication statusPublished - 2011

Keywords

  • Animals
  • Behavior, Animal
  • Brain
  • Cholestenone 5 alpha-Reductase
  • Female
  • FERTILITY
  • MEMORY
  • Pregnancy
  • Progestins
  • RATS
  • Rats, Long-Evans

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