Recovery of fertility in quinestrol-treated or diethylstilbestroltreated mice:Implications for rodent management

Fertility control is an alternative strategy to traditional culling for the management of rodent pests.Previous studies have demonstrated that quinestrol is a potential contraceptive for male rodents,but the recovery of fertility in quinestrol-treated rodents has not been evaluated.This study used C57BL/6J mice to evaluate the recovery rate of male fertility after the administration of quinestrol.Diethylstilbestrol(DES),a non-steroid estrogenic compound,was used for comparison.Different groups of mice were treated with 1 mg/kg quinestrol,1 mg/kg DES,or castor oil separately for 7 days.These mice were then killed on days 8,22 and 50 respectively.Our results indicated that the weight of epididymides and seminal vesicles decreased significantly on days 8 and 22 in quinestrol/DES-treated mice,with extensive histological changes in the seminiferous tubules.Sperm concentrations in the cauda epididymal fluid were significantly reduced on days 8 and 22 in both quinestrol and DES treatment groups and on day 50 for the DES,but not the quinestrol group.Further analysis revealed that DES-treated mice exhibited a higher proportion of abnormal sperm accumulation in the epididymis,indicating that the normal sperm transportation to the cauda epididymis was blocked.Our results indicate that the anti-fertility effects on male mice given quinestrol were of shorter duration than for those receiving DES at the dose of 1 mg/kg body weight.

A novel missense variant in ACAA1 contributes to early-onset Alzheimer’s disease,impairs lysosomal function,and facilitates amyloid-p pathology and cognitive decline

Alzheimer’s disease(AD)is characterized by progressive synaptic dysfunction,neuronal death,and brain atrophy,with amyloid-p(Ap)plaque deposits and hyperphosphorylated tau neurofibrillary tangle accumulation in the brain tissue,which all lead to loss of cognitive function.Pathogenic mutations in the well-known AD causal genes including APP,PSEN1,and PSEN2 impair a variety of pathways,including protein processing,axonal transport,and metabolic homeostasis.Here we identified a missense variant rs117916664(c.896T>C,p.Asn299Ser[p.N299S])of the acetyl-CoA acyltransferase 1(ACM1)gene in a Han Chinese AD family by whole-genome sequencing and validated its association with early-onset familial AD in an independent cohort.Further in vitro and in vivo evidence showed that ACAA1 p.N299S contributes to AD by disturbing its enzymatic activity,impairing lysosomal function,and aggravating the Ap pathology and neuronal loss,which finally caused cognitive impairment in a murine model.Our findings reveal a fundamental role of peroxisome-mediated lysosomal dysfunction in AD pathogenesis.