Work

Ammonium chloride, an environmental pollutant, disrupts melanocyte biology through the regulation of melanosome and autophagy

Year: 2025

Type: article

Abstract: Ammonium chloride is an indoor environmental pollutant released due to industrial emissions, concrete, indoor bacteria, or other sources. In this study, we characterized molecular mechanisms of ammonium chloride-induced cell damage in melanocyte cells, which are a critical effector for pigmentation. Specifically, we investigated the effects of ammonium chloride on pigmentation and its underlying mechanisms, including its involvement in melanogenesis and autophagy. Based on the experiments, we elucidated that ammonium chloride induced and increased melanogenesis by upregulating MITF via AKT-mediated melanogenic signaling pathways. Moreover, ammonium chloride did not exhibit lysosomotropic activity and inhibited autophagy by activating the AKT-mTOR signaling pathway, suggesting that the pigment-regulating mechanism of ammonium chloride was associated with autophagy in pigmented cells. The findings of this study offer new perspectives on the mechanisms involved in ammonium chloride-induced pigmentation and propose a potential approach to mitigate ammonium chloride-induced side effects like hyperpigmentation and hyperammonemia by employing a combined autophagy inducer. Ammonium chloride increases phosphorylation of AKT which regulates both melanogenesis and melanosome degradation. AKT activated by ammonium chloride phosphorylates p38 and reduces phosphorylation of p44/42, leading to melanogenesis. The phosphorylated AKT also promotes melanogenesis by inhibiting the phosphorylation of FoxO3a and activating phosphorylated GSK3beta-dephosphorylated beta-catenin signaling pathway. In addition, ammonium chloride-induced phosphorylation of AKT regulates autophagy. It inhibits the phosphorylation of AMPK and increases the phosphorylation of mTOR, which increases the phosphorylation of ULK1 and inhibits the initiation of autophagy via ULK1. Therefore, the degradation process of melanosomes by autophagy is suppressed and melanosomes are accumulated. Adobe illustrator was used to draw the illustration. • Ammonium chloride increased pigmentation by activating AKT-mediated melanogenic signalings. • Ammonium chloride inhibited autophagy by activating the AKT-mTOR signaling pathway. • The AKT-mTOR pathway provides a target for mitigating the adverse effects of ammonium chloride. • Autophagy could be a novel therapeutic strategy for ammonium chloride-induced hyperpigmentation.

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2025.118214