Effects of melamine on pregnant dams and embryo‐fetal development in rats

Abstract

There are worldwide concerns regarding the potential adverse effect of melamine. This study investigated the potential effects of melamine on pregnant dams and embryo-fetal development in Sprague-Dawley rats following maternal exposure on gestational days (GD) 6-20. Melamine was administered to pregnant rats by gavage at doses of 0, 200, 400 and 800 mg kg⁻¹ per day (n = 8-10 for each group). All dams were subjected to a Caesarean section on GD 21 and their fetuses were examined for morphological abnormalities. With administration of melamine at 800 mg kg⁻¹ per day, maternal toxicity manifested as increased incidences of clinical signs and death, lower body weight gain and food intake, and increases in heart, adrenal gland and kidney weights. Histopathological examinations revealed an increase in incidences of congestion, tubular necrosis/degeneration, crystals, casts, inflammatory cells in tubules, tubular dilation and tubular hyaline droplets in the maternal kidneys, while fetal kidneys (one fetus/litter) did not show any histopathological changes. Developmental toxic effects included a decrease in fetal weight, an increase in the incidence of skeletal variations and a delay in fetal ossification. No treatment-related maternal or developmental effects were observed at doses ≤ 400 mg kg⁻¹ per day. These results show that 15-day repeated oral dosing of melamine is embryo-/fetotoxic at a maternotoxic dose, but not teratogenic in rats. The no-observed-adverse-effect level of melamine for pregnant dams and embryo-fetal development is considered to be 400 mg kg⁻¹ per day.

Use of urinary renal biomarkers to evaluate the nephrotoxic effects of melamine or cyanuric acid in non-pregnant and pregnant rats

“…For SCr and BUN, the statistically significant difference between non-pregnant and pregnant rats on Day 10 is likely due to the fact that melamine induced less toxic effects in the non-pregnant animals combined with the insensitivity of these biomarkers to detect renal damage until a significant portion of renal function is lost. These results are also in agreement with the conclusions by Kim et al (2011) and Stine et al (2014) that pregnancy increases susceptibility to the renal toxic effects of melamine in rats. These results also indicate that the biomarkers can detect and differentiate the severity of effects induced by high concentrations of melamine or cyanuric acid at earlier time points.…”

“…In a doserange finding study, Kim et al (2011) observed that dams administered 1600 mg/kg bw/day of melamine for 15 days experienced severe adverse effects compared to those treated at lower doses. The present study was conducted to evaluate the ability of urinary Kim-1, clusterin, and osteopontin to detect and differentiate the nephrotoxic effects of 1000 mg/kg bw/day of melamine or cyanuric acid administered via gavage in non-pregnant and pregnant female rats for 10 consecutive days.…”

“…Most studies in pregnant rats have involved single-dose pharmacokinetic analyses or evaluated melamine alone (Chan et al, 2011;Chu and Wang, 2013;Chu et al, 2010;Jingbin et al, 2010;Kim et al, 2011). The present study employed repeated extremely high oral doses of either melamine or cyanuric acid in non-pregnant and pregnant rats and investigated the performance of several of the recently identified urinary renal biomarkers of AKI in detecting and differentiating the effects of melamine and cyanuric acid.…”

Development of analytical method of melamine in placenta from pregnant women by isotope‐dilution liquid chromatography/tandem mass spectrometry

“…In mammals, mother and fetal compartments are separated by the placenta, an organ that connects the developing fetus to the uterine wall and the only source of nutrients from the pregnant mother . Animal studies, which have detected melamine in the placentas, amniotic fluid, and even fetus or neonatal kidney in rats, have concluded that melamine can cross the placental barrier and enter the fetus …”

Melamine Impairs Renal and Vascular Function in Rats

“…Importantly, we showed that melamine is able to retain in the offspring after 3 months, indicating a potential long-term renal damage or likely a predisposition to other kidney diseases. However, we do not have the data to show whether and how embryo is exposed to melamine and also to cyanuric acid, although higher dose is considered to be both embryotoxic and maternotoxic202122. These findings raise the health concern of monitoring melamine-contaminated food for mothers.…”