Effects of melamine and cyanuric acid on placental and fetal development in rats.

Melamine or cyanuric acid alone has low toxicity, but combined exposure to melamine and cyanuric acid was reported to cause unexpected toxicological effects. This study investigated the potential effects and toxic mechanism of combined exposure to melamine and cyanuric acid on placental and fetal development in rats. Exposure to melamine and cyanuric acid caused maternal toxicity manifested by increased abnormal symptoms and decreased body weight gain. Developmental toxic effects included a decrease in placental and fetal weights with increased fetal deaths and post-implantation loss. Melamine and cyanuric acid induced oxidative stress in the developing placenta and fetus. The placentas from rats treated with melamine and cyanuric acid showed shortening of the placental layers with histological changes, decreased cell proliferation, increased apoptotic changes, and decreased insulin-like growth factor (IGF)/IGF-binding proteins (IGFBPs) and placental lactogen (PL) expression levels. Fetuses from melamine- and cyanuric acid-treated dams showed increased apoptotic changes and suppressed cellular proliferation in their livers and vertebrae. Consequently, combined exposure to melamine and cyanuric acid resulted in high levels of oxidative stress and impaired placental development associated with impairment of the IGF/IGFBP and PL systems, resulting in increased apoptotic changes and reduced fetal cell proliferation.