Excessive maternal methionine intake increases the incidence of congenital anomalies of the kidney and urinary tract in offspring mice

Imbalance of maternal diets can impair offspring development and contribute to congenital anomalies of the kidney and urinary tract (CAKUT). Excess maternal methionine intake is known to impair fetal development. The placenta serves as a crucial interface for maternal–fetal exchange and may contribute to these adverse outcomes. We hypothesize that excess methionine intake during pregnancy in mice increases the incidence of CAKUT in offspring. Therefore, we established a mouse model of 10% (w/w) methionine intake during pregnancy from Embryonic Day 8.5 to11.5 (E8.5-E11.5) and assessed the kidney phenotype. Crucial kidney developmental pathways were analyzed by RT–qPCR and immunofluorescence at E11.5. Changes in methionine metabolism in maternal plasma and placental tissues at E11.5 were analyzed using liquid chromatography–tandem mass spectrometry, and placental RNA–seq was performed. Offspring from dams exposed to excess methionine exhibited increased incidence of CAKUT (relative risk = 4.15, 95% confidence interval: 1.40-12.34, P = .010), 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, homocysteine was elevated in the placentas, together with decreased mRNA expression of key metabolic enzymes betaine-homocysteine S-methyltransferase (Bhmt) and cystathionine γ-lyase (Cth) in the placentas. Concurrently, RNA-seq of E11.5 placentas revealed alterations in immune-inflammatory and vascular-related pathways. Overall, 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 placental homocysteine.