Cadmium reduces growth of male fetuses by impairing development of the placental vasculature and reducing expression of nutrient transporters

Abstract

In utero exposure to the toxic metal cadmium (Cd) alters fetoplacental growth in rodents and has been inversely associated with birth weight and infant size in some birth cohorts. Moreover, studies suggest that Cd may have differential effects on growth and development according to offspring sex. The purpose of the current study was to evaluate changes in male and female fetoplacental development following a single injection of saline (5 ml/kg ip) or cadmium chloride (CdCl₂, 2.5, 5 mg/kg, ip) on gestational day (GD) 9. By GD18, no changes in fetal or placental weights were observed after treatment with 2.5 mg/kg CdCl₂. By comparison, the weight and length of male fetuses and their placentas were reduced following treatment with 5 mg/kg CdCl₂ whereas no change was observed in females. In addition, the area of maternal and fetal blood vessels as well as the expression of the glucose transporters, Glut1 and Glut3, and the endothelial marker, CD34, were reduced in the placentas of CdCl₂-treated male offspring compared to females. Interestingly, the placentas of females accumulated 80% more Cd than males after CdCl₂ (5 mg/kg) administration. Female placentas also had higher concentrations of zinc and the zinc transporter Znt1 compared to males which may explain the limited changes in fetal growth observed following CdCl₂ treatment. Taken together, disruption of vasculature development and reduced expression of glucose transporters in the placenta provide potential mechanisms underlying reduced fetal growth in male offspring despite the greater accumulation of Cd in female placentas.

Keywords: Cadmium; Fetal growth restriction; Fetal sex; Placenta; Placental vasculature.