Acute Oral, Subacute, and Developmental Toxicity Profiling of Naphthalene 2-Yl, 2-Chloro, 5-Nitrobenzoate: Assessment Based on Stress Response, Toxicity, and Adverse Outcome Pathways.

Atta Ur Rehman,Sarfraz Ahmad,Tariq Ismail,Uzma Saleem,Muhammad Usman Mirza,Bashir Ahmad,Fareeha Anwar

doi:10.3389/fphar.2021.810704

Abstract

The U.S. National Research Council (NRC) introduced new approaches to report toxicity studies. The NRC vision is to explore the toxicity pathways leading to the adverse effects in intact organisms by the exposure of the chemicals. This study examines the toxicity profiling of the naphthalene-2-yl 2-chloro-5-dinitrobenzoate (SF5) by adopting the vision of NRC that moves from traditional animal studies to the cellular pathways. Acute, subacute, and developmental toxicity studies were assayed according to the Organization for Economic Cooperation and Development (OECD) guidelines. The stress response pathway, toxicity pathway, and adverse effects outcome parameters were analyzed by using their standard protocols. The results showed that the acute toxicity study increases the liver enzyme levels. In a subacute toxicity study, alkaline phosphatase (ALP) levels were raised in both male and female animals. SF5 significantly increases the normal sperm count in the male animals corresponding to a decrease in the abnormality count. Developmental toxicity showed the normal skeletal and morphological parameters, except little hydrocephalus was observed in developmental toxicity. Doses of 20 mg/kg in males and 4 mg/kg in females showed decreased glutathione (GSH) levels in the kidney and liver. MDA levels were also increased in the kidney and liver. However, histopathological studies did not show any cellular change in these organs. No statistical difference was observed in histamine levels, testosterone, nuclear factor erythroid two-related factor-2 (Nrf2), and nuclear factor-kappa B (NF-κB), which showed no initiation of the stress response, toxicity, and adverse effect pathways. Immunomodulation was observed at low doses in subacute toxicity studies. It was concluded that SF5 did not produce abrupt and high-toxicity levels in organs and biochemical parameters. So, it is safe for further studies.

Highlights

The treatment of neurodegenerative diseases primarily includes control rather than cure due to potentially irreversible changes in the brain (Hussain et al, 2018)
The Organization for Economic Cooperation and Development (OECD) and NRL guidelines recommendation provides the initial screening of chemical compounds in a scientifically acceptable way, i.e., acute, subacute, developmental toxicity, subchronic, and chronic toxicity performance and on the basis of the different toxicity pathways, respectively
This study concluded that LD50 of SF5 is higher than 2,000 mg/kg as no mortality was observed at this dose

Summary

Introduction

The treatment of neurodegenerative diseases primarily includes control rather than cure due to potentially irreversible changes in the brain (Hussain et al, 2018). The anti-neurodegenerative drugs are usually used to alleviate symptoms or to retard disease progression. The prognosis of these diseases requires long-term, sometimes a lifetime, administration of the drugs. An anti-neurodegenerative drug must have a reliable safety profile, enabling it suitable for long-term administration. In a drug discovery pipeline, preclinical toxicity analyses are of paramount significance for a drug to reach clinical practice. Based on the duration of the drug administration, preclinical toxicity studies are divided into acute toxicity, subacute toxicity, developmental toxicity, subchronic toxicity, genotoxicity, developmental toxicity, reproductive toxicity, cytotoxicity, and chronic toxicity. The conclusive goal of the toxicity studies is to correlate the animal responses toward humans (Gad, 2008)

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Discussion

Conclusion