Zone-Specific Histopathological Remodeling of the Maternal Placental Fetal Axis Following Gestational Exposure to Aspartame: Apoptosis Dynamics, Placental Microenvironment Disruption, and Fetal Developmental Consequences in a Mammalian Model

Abstract

Aspartame (APM) is one of the most extensively used artificial sweeteners worldwide, yet its safety during gestation remains poorly defined. The growing feto-placental unit might be more susceptible to oxidative stress and programmed cell death triggered by xenobiotics. Objective: The present research aims to characterise the histopathological and biochemical harm generated by aspartame along the maternal-placental-fetal (MPF) axis in a zone-specific manner in a rat model and to evaluate whether N-acetylcysteine (NAC) might ameliorate these effects. Methods: Forty pregnant Wistar albino rats were divided into five groups (n=8): distilled-water control, aspartame at 125, 250 or 500 mg/kg/day (oral gavage, gestational days 1-20) and aspartame 500 mg/kg plus NAC 150 mg/kg. On the 20th day of gestation, the mothers' and foetuses' livers and placentas were excised. Apoptotic index was mapped by TUNEL test, oxidative damage was assessed by quantification of malondialdehyde (MDA) and enzymatic activity of caspase-3 was determined. Foetal morphometric characteristics and hepatic microarchitecture were assessed. Results: Aspartame caused substantial dose-dependent increases in apoptotic index in maternal liver (up to 22.3 ± 1.8%), foetal liver (up to 31.4 ± 2.2%), placental labyrinth zone (24.6 ± 2.1%) and junctional zone (17.3 ± 1.5%) all considerably larger than control (p < 0.001). Indices for foetal tissues were consistently higher than for maternal equivalents, demonstrating a gradient of developmental vulnerability. Dose-response curves for MDA and Caspase-3 were parallel. At the maximum dosage, foetal body weight and liver somatic index were considerably decreased. Co-treatment with NAC significantly decreased all the observed endpoints (p < 0.05 vs. Asp-High). Conclusions: Gestational exposure to aspartame alters the MPF axis in a dose-dependent and zone-specific way, and foetuses are more sensitive than dams. The mitigation caused by NAC suggests a considerable role of oxidative stress to the observed damage. These results are of considerable concern about the intake of APM in pregnancy.