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. 2022 Jan 20:12:810704.
doi: 10.3389/fphar.2021.810704. eCollection 2021.

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

Fareeha Anwar  1   2 , Uzma Saleem  3 , Atta Ur Rehman  4 , Bashir Ahmad  1   2 , Tariq Ismail  5 , Muhammad Usman Mirza  6 , Sarfraz Ahmad  7
Affiliations

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

Fareeha Anwar et al. Front Pharmacol. .

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.

Keywords: Nrf2; SF5; acute oral toxicity; biochemical parameters; oxidative stress markers; stress response pathway.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Chemical structure of SF5.
FIGURE 2
FIGURE 2
Effect of SF5 on body weights of rats in different toxicity studies.
FIGURE 3
FIGURE 3
Histopathology of the selected organs in acute oral toxicity (2,000 mg/kg).
FIGURE 4
FIGURE 4
Effect of SF5 on body weights of rats in the subacute toxicity study.
FIGURE 5
FIGURE 5
Effect of SF5 treatment on liver function, kidney function, and lipid profile in both males and females at different dose levels. **p < 0.01 and ***p < 0.001 given in comparison to the control.
FIGURE 6
FIGURE 6
Effect of repeated-dose administration of a different dose of SF5 on histamine, NF-κB, and Nrf2 levels in the serum of the treated animals in subacute toxicity studies. Data are presented as mean ± SEM, n = 3, ***p < 0.01 compared to the control.
FIGURE 7
FIGURE 7
Estimation of oxidative stress markers in the subacute toxicity study in male and female rats. Data are presented as mean ± SEM, n = 3. *p < 0.05 is the increase in the level of significance while ^p < 0.05 is the level of decrease in comparison to the control.
FIGURE 8
FIGURE 8
Histopathological analysis of different organs in subacute toxicity studies of SF5 at 5, 10, 20, and 40 mg/kg dose levels.
FIGURE 9
FIGURE 9
Effect of SF5 on body weights of rats in the developmental toxicity study.
FIGURE 10
FIGURE 10
Soft tissue examination of fetus through Bouin fixation in the developmental toxicity study.
FIGURE 11
FIGURE 11
Skeletal anomalies of the animals treated with SF5 (40 mg/kg) during developmental toxicity study.
FIGURE 12
FIGURE 12
Pictorial view of morphological parameters of sperm.
FIGURE 13
FIGURE 13
Effect of repeated-dose administration of a different dose of SF5 on testosterone levels in the serum of the treated animals in the subacute toxicity study. Data are presented as mean ± SEM, n = 3, ***p < 0.01 compared to the control.
FIGURE 14
FIGURE 14
Histopathology of the selected organs in the developmental toxicity study (40 mg/kg).
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