Acrylamide is a class 2A carcinogen with neurotoxicity and genotoxicity. In addition to industrial production, it is ubiquitous in high-temperature heated high-carbohydrate foods. Numerous studies have confirmed the toxicity of ACR on reproduction. Implantation and decidualization are crucial processes during the establishment of pregnancy in rodents and humans. However, its effect on uterine implantation and decidualization remains poorly understood. The objective of this study is to elucidate the mechanism by which ACR affects implantation and decidualization in mice. ACR is exposed in the daily drinking water of female mice, and the dose is calculated according to the body weight of the mice. After 3 months of administration at concentrations of 0, 20, and 30 mg ACR/kg/d, female mice are mated with male mice to induce pregnancy. Compared to the control group, ACR treatment significantly reduces the number of embryo implantations and litter size. ACR treatment leads to abnormal expression of endometrial receptivity-related molecules in the luminal epithelium on day 4 of pregnancy, including a decrease in p-STAT3 level and an increase in MUC1 and MSX1 levels. The level of decidualization-related molecules is obviously downregulated by ACR. Furthermore, ACR treatment results in abnormality of oxidative stress- and ferroptosis-related protein levels at the implantation site on day 5. In conclusion, acrylamide can impair mouse implantation and decidualization by disrupting oxidative stress and ferroptosis.

The supply of amino acids is essential to embryo survival and successful pregnancy. The accumulating evidence indicates that arginine, a semi-essential amino acid, plays a key role during early pregnancy. Arginase (ARG2) is a key enzyme for catalyzing arginine into ornithine and urea. However, the expression, regulation, and role of arginase during early mouse pregnancy are still unknown. In our study, ARG1 immunofluorescence is mainly detected in uterine epithelium and gradually decreases from days 1 to 5 of pregnancy. From days 1 to 4 of pregnancy, there is no detectable ARG2 immunofluorescence in the mouse uterus. On day 5 of pregnancy, ARG2 signals are strongly seen in the primary decidua surrounding the implanting blastocyst at the implantation site, but not at the inter-implantation site. There is a temporary increase for ARG2 levels under mouse in vitro decidualization, suggesting ARG2 may be involved in the initiation of mouse decidualization. Prl8a2, a marker of mouse in vitro decidualization, is significantly decreased after ARG levels are suppressed. However, Arg2 overexpression obviously increases Prl8a2 levels. Mouse in vitro decidualization is downregulated by arginine and ornithine but stimulated by a low dose of urea. Urea has a beneficial effect on uterine receptivity and antioxidative enzymes. Our results indicate that ARG2 plays an important role during mouse decidualization by balancing the levels of arginine, ornithine, and urea.