The transgenerational effects of maternal low-protein diet during lactation on offspring

Environmental factors such as diet and lifestyle can influence the health of both mothers and offspring.However,its transgenerational transmission and underlying mechanisms remain largely unknown.Here,using a maternal lactation-period low-protein diet(LPD)mouse model,we show that maternal LPD during lactation causes decreased survival and stunted growth,significantly reduces ovulation and litter size,and alters the gut microbiome in the female LPD-F1 offspring.The transcriptome of LPD-F1 metaphase II(MII)oocytes shows that differentially expressed genes are enriched in female pregnancy and multiple metabolic processes.Moreover,maternal LPD causes early stunted growth and impairs metabolic health,which is transmitted over two generations.The methylome alteration of LPD-F1 oocytes can be partly transmitted to the F2 oocytes.Together,our results reveal that LPD during lactation transgenerationally affects offspring health,probably via oocyte epigenetic changes.

DENND1A desensitizes granulosa cells to FSH by arresting intracellular FSHR transportation

Polycystic ovary syndrome(PCOS)is a complex disorder.Genome-wide association studies(GWAS)have identified several genes associated with this condition,including DENND1A.DENND1A encodes a clathrin-binding protein that functions as a guanine nucleotide exchange factor involved in vesicular transport.However,the specific role of DENND1A in reproductive hormone abnormalities and follicle development disorders in PCOS remain poorly understood.In this study,we investigated DENND1A expression in ovarian granulosa cells(GCs)from PCOS patients and its correlation with hormones.Our results revealed an upregulation of DENND1A expression in GCs from PCOS cases,which was positively correlated with testosterone levels.To further explore the functional implications of DENND1A,we generated a transgenic mouse model overexpressing Dennd1a(TG mice).These TG mice exhibited subfertility,irregular estrous cycles,and increased testosterone production following PMSG stimulation.Additionally,the TG mice displayed diminished responsiveness to FSH,characterized by smaller ovary size,less well-developed follicles,and abnormal expressions of FSH-priming genes.Mechanistically,we found that Dennd1a overexpression disrupted the intracellular trafficking of follicle stimulating hormone receptor(FSHR),promoting its internalization and inhibiting recycling.These findings shed light on the reproductive role of DENND1A and uncover the underlying mechanisms,thereby contributing valuable insights into the pathogenesis of PCOS and providing potential avenues for drug design in PCOS treatment.