Impact of Perfluorooctane Sulfonate on Reproductive Ability of Female Mice through Suppression of Estrogen Receptor α-Activated Kisspeptin Neurons.

Perfluorooctane sulfonate (PFOS) is used extensively in industrial and household applications. High exposure to PFOS has been associated with increased odds of irregular and long menstrual cycles in women. However, the underlying mechanisms remain to be elucidated. Herein, we show that adult female mice appeared prolongation of diestrus and reduction of corpora luteum within a week of oral administration of PFOS (10 mg/kg), which are associated with decreases in the levels of serum progesterone, LH and hypothalamic GnRH. The number of AVPV-kisspeptin neurons and the AVPV-kisspeptin expression were increased in proestrus mice or OVX-mice treated with high-dose estradiol benzoate (0.05 mg/kg), which were suppressed by the administration of PFOS. The administration of PFOS or GPR54 antagonist P234 prevented the generation of LH-surge in OVX-mice treated with high-dose E2. In hypothalamic slices incubated in 100 nM E2 for 4 h, the AVPV-kisspeptin expression was significantly enhanced, which was inhibited by PFOS in a dose-dependent manner or estrogen receptor α (ERα) antagonist MPP, but not ERß antagonist PHTPP. The incubation of ERα agonist PPT rather than ERß agonist DPN could increase the level of AVPV-kisspeptin expression, which was sensitive to the treatment with PFOS. The administration of GPR54 agonist kisspeptin-10 in PFOS-mice could correct the prolongation of diestrus and reduction of corpora luteum, and recover the LH-surge and the levels of LH and GnRH. The results indicate that exposure to PFOS suppressed ERα-induced activation of AVPV-kisspeptin neurons leads to diestrus prolongation and ovulation reduction.

Treatment with progesterone after focal cerebral ischemia suppresses proliferation of progenitor cells but enhances survival of newborn neurons in adult male mice.

Stroke stimulates cell proliferation in the subventricular zone (SVZ) and hippocampal dentate gyrus (DG) in adult rodents and humans. However, most newborn cells will die within 1-2 weeks. We recently have revealed that progesterone (P4) promotes the survival of newborn neurons in the DG and improves the neurological dysfunction after cerebral ischemia. The aim of this study was to further explore the effects of P4 on the ischemia-induced neurogenesis in the DG, SVZ and striatum. Bromodeoxyuridine (BrdU) was used to label proliferating cells on day 3 after middle cerebral artery occlusion (MCAO). P4 (4 mg/kg) was injected for 3 consecutive days at BrdU-D(-1 to 1) (from one day before to one day after BrdU-injection) or BrdU-D(4-6) (4-6 days after BrdU-injection). The P4-treatment at BrdU-D(-1 to 1) attenuated the increase in the density of 24-h-old BrdU(+) cells in MCAO-DG and -SVZ, which was blocked by the 5alpha-reductase inhibitor finasteride. The P4-treatment at BrdU-D(4-6) significantly increased the density of 28-day-old BrdU(+) cells in MCAO-DG without changing the population ratios of BrdU(+)/NeuN(+) and BrdU(+)/GFAP(+) cells, which was sensitive to the blockade of P4 receptor and extracellular signal-regulated kinase (ERK). In addition, the P4-treatment at BrdU-D(4-6) produced approximately 2-fold increase in the density of 28-day-old BrdU(+) cells in MCAO-striatum. This study provides evidence that the P4-treatment after stroke suppresses ischemia-stimulated proliferation of progenitor cells but improves the poor survival of ischemia-induced newborn cells.