Excessive Maternal Methionine Intake Increases the Incidence of CAKUT in Mice

Background: Imbalance of maternal diets can impair offspring development and contribute to congenital anomalies of the kidney and urinary tract (CAKUT). The placenta serves as a crucial interface for maternal-fetal exchange and may contribute to these adverse outcomes. Although excess maternal methionine intake is known to impair fetal development, its specific association with CAKUT remains unclear.Objective: To investigate the association between excess maternal methionine intake during pregnancy and the incidence of CAKUT and the potential mechanisms.Methods: A mouse model of 10% excess methionine intake during pregnancy was established. Maternal status and the kidney development outcomes in offspring were assessed. Crucial kidney developmental pathways were analyzed by RT-qPCR and immunofluorescence at Embryonic Day 11.5 (E11.5). Changes in methionine metabolism (methionine, homocysteine, cystathionine) in maternal plasma and placental tissues at E11.5 were analyzed using liquid chromatography-tandem mass spectrometry, and placental RNA-seq was performed.Results: Offspring from dams exposed to 10% excess methionine from E8.5-E11.5 exhibited a significantly increased incidence of CAKUT (39.53% vs. 9.52%, p = 0.0021), primarily presenting as hydronephrosis and/or duplex collecting system. E11.5 embryonic kidneys showed shorter common nephric duct and decreased activity of the Gdnf/Ret/p-Akt pathway. At E11.5, while plasma levels of methionine and related metabolites were unchanged, homocysteine and cystathionine were elevated in the placentas, together with decreased mRNA levels of their key metabolic enzymes betaine-homocysteine S-methyltransferase (Bhmt) and cystathionine y-lyase (Cth) in the placentas. Concurrently, RNA-seq of E11.5 placentas revealed alterations in immune-inflammatory and vascular-related pathways.Conclusion: Excessive maternal methionine intake in mice increased the incidence of CAKUT in offspring, which may be associated with altered activity of the Gdnf/Ret/PI3K-p-Akt pathway in embryonic kidneys as well as elevated homocysteine in placentas.