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Time-dependent biphasic dysregulation of autophagy and innate immunity underlies polystyrene microplastics-induced hepatotoxicity in Nile tilapia
Summary
Researchers tracked Nile tilapia liver responses to polystyrene microplastics over 21 days, revealing a biphasic pattern in which early autophagy induction preceded innate immune activation at 14 days, followed by broad suppression of both pathways by day 21 — with pharmacological autophagy inhibition confirming that autophagy directly triggers the subsequent inflammatory cascade.
The immunotoxicity of microplastic pollution in aquatic species is an issue of growing concern. However, the time course and mechanistic crosstalk underlying microplastic-induced hepatic injury remain poorly defined. This study examined the temporal hepatic response of Nile tilapia (Oreochromis niloticus) to 100 nm polystyrene microplastics (PS) over a 21-day exposure period, covering acute (7 days) and sub-chronic (14 and 21 days) phases. Histopathological evaluation showed no obvious liver lesions in exposed fish relative to controls at 7 days post-exposure (dpe). In contrast, progressive tissue damage marked by enhanced inflammatory cell infiltration was apparent at 14 and 21 dpe. PS exposure triggered time-dependent oxidative stress, with reactive oxygen species (ROS) and malondialdehyde (MDA) levels significantly increased and superoxide dismutase (SOD) activity decreased at 14 and 21 dpe. Ultrastructural analysis using transmission electron microscopy (TEM) further revealed distinct mitochondrial swelling and a notable increase in autophagosome numbers within hepatocytes at 7 and 14 dpe. Transcriptomic profiling indicated a biphasic dysregulation affecting both autophagy and inflammatory pathways. Specifically, autophagy-related pathways were significantly upregulated by 7 dpe, which preceded the marked activation of innate immune signaling pathways, such as NOD-like receptors (NLR) and mitogen-activated protein kinase (MAPK) signaling, observed at 14 dpe. After prolonged exposure to 21 dpe, both autophagic and inflammatory pathways were downregulated. qPCR confirmed this time-dependent expression profile for key genes associated with autophagy (sqstm1, map1lc3b, atg4d, atg5, becn1) and immune (il1β, nlrp3, tgfβ, map3k7, tnfa, tnfb, myd88) function. Pharmacological inhibition of autophagy by 3-methyladenine (3-MA) markedly abrogated the activation of NLR and MAPK signaling genes at 14 dpe, confirming a causal regulatory link between autophagy and innate immunity. Collectively, these findings suggest that microplastic exposure triggers a sequential immunotoxic transition in the fish liver. The early induction of autophagy may support subsequent immune activation, which eventually shifts to a broad suppression of immune pathways under sustained stress. This study offers new insight into the dynamic interaction between autophagy and innate immunity during microplastic-induced hepatotoxicity and highlights the potential risk of immunosuppression after long-term microplastic exposure.