The effects of gestational and lactational exposure to Nonylphenol on c-jun, and c-fos expression and learning and memory in hippocampus of male F1 rat

Document Type : Original Article


1 School of Public Health, Zunyi Medical University, Zunyi Guizhou 563099, P.R. of China

2 Department of Nuclear Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi Guizhou 563099, P.R. of China


Objective(s): To investigate the effects of Nonylphenol (NP) in pups from dams exposed during gestational and lactational periods on immediate early genes (c-jun, c-fos) in hippocampus and the learning and memory of F1 rats.
Materials and Methods: Twenty eight pregnant dams, stratified by pregnancy date, were randomly assigned into 4 groups, which were gavaged with NP at the doses of 50 mg/kg/day, 100 mg/kg/day, 200 mg/kg/day and groundnut oil, respectively. Step-down avoidance test, and learning and memory effects of NP were evaluated on 8-weeks-old pups. The expressions of c-jun and c-fos and the activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AchE) were evaluated in hippocampus of pups.
Results: Compared to the control, reaction time (RT) that pups spent to jump to the platform was longer (P=0.02), the number of errors were higher (P=0.01), and the step-down latency  was shorter in the 200 mg/kg/day NP-treated group (P=0.04). Exposure to NP induced a significant reduction in ChAT activity in hippocampus in the 100 (P=0.005) and 200 mg/kg/day NP-treated groups (P=0.002), whereas exposure to 200 mg/kg/day caused a significant increase in AchE activity (P=0.004); a dose–response relationship was revealed between ChAT and AchE activities and NP exposure in the hippocampus of pups (r=-0.821, P=0.01; r=0.757, P=0.04). Exposure to NP in the 100 and 200 mg/kg/day NP-treated groups exhibited an increase in number of c-fos and c-jun positive cells.
Conclusion: Exposure to NP might negatively affect learning and memory ability in F1 rats, possibly due to the alterations in the expression of c-jun and c-fos, and ChAT, AchE activities in hippocampus of pups.


1.Jie X, Yang W, Jie Y, Fan QY, Liu XY, Yan L, et al. Immune effects of nonylphenol on offspring of rats Exposed During Pregnancy. Hum Ecol Risk Assess 2010; 16:444–452.
2.Yu Jie, Fan QY, Binli H, Biao Z, Zheng F, Jianmei L, et al. Joint neurodevelopmental and behavioral effects of nonylphenol and estradiol on F(1) male rats. Int J Environ Heal R 2013; 23:321-330.
3.White R, Jobling S, Hoare S, Sumpter J, Parker M. Environmentally persistent alkylphenolic compounds are estrogenic. Endocrinology 2014; 135:175–182.
4.Perez-Cadahia B, Drobic B, Davie JR. Activation and function of immediate-early genes in the nervous system. Biochem Cell Biol 2011; 89:61–73.
5.Kubik S, Miyashita T, Guzowski JF. Using immediate-early genes to map hippocampal subregional functions. Learn Mem 2007; 14:758–770.
6.Jie X, Yang W, Jie Y, Hashim JH, Liu XY, Fan QY, et al. Toxic effect of gestational exposure to nonylphenol on F1 male rats. Birth Defects Res B Dev Reprod Toxicol 2010; 89:418–428.
7.Hollnagel JO, Ul Haq R, Behrens CJ, Maslarova A, Mody I, Heinemann U. No evidence for role of extracellular choline-acetyltransferase in generation of gamma oscillations in rat hippocampal slices in vitro. Neuroscience 2015; 284:459-469.  
8.Uyanıkgil Y, Turgut M, Baka M. Effects of melatonin on the cerebellum of infant rat following kaolin-induced hydrocephalus: a histochemical and immunohistochemical study. Cerebellum 2017; 16:142-150.   
9.Jie Y, Xuefeng Y, Mengxue Y, Xuesong Y, Jing Y, Yin T, et al. Mechanism of nonylphenol-induced neurotoxicity in F1 rats during sexual maturity. Wien Klin Wochenschr 2016; 128:426-434.
10.Thomas JD, La Fiette MH, Quinn VR, Riley EP. Neonatal choline supplementation ameliorates the effects of prenatal alcohol exposure on a discrimination learning task in rats. Neurotoxicol Teratol 2000; 22:703-711.
11.Vasilopoulou CG, Constantinou C, Giannakopoulou D, Giompres P, Margarity M. Effect of a1dult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice.  Physiol Behav 2016; 164:284-291.
12.Hirshman CA, Bergman NA. Factors influencing intrapulmonary airway calibre during anaesthesia. Br J Anaesth 1990; 65:30-42.
13.Ludwig M, Tobin VA, Callahan MF, Papadaki E, Becker A, Engelmann M, et al. Intranasal application of vasopressin fails to elicit changes in brain immediate early gene expression, neural activity and behavioural performance of rats. J Neuroendocrinol 2013; 25:655-667. 
14.Herdegen T, Skene P, Bähr M. The c-Jun transcription factor–bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci 1997; 20:227-231.    
15.Mirante O, Price M, Puentes W, Castillo X, Benakis C, Thevenet J, et al. Endogenous protease nexin-1 protects against cerebral ischemia. Int J Mol Sci 2013; 14:16719-16731.   
16.Arthur-Farraj PJ, Latouche M, Wilton DK, Quintes S, Chabrol E, Banerjee A, et al. c-Jun reprograms schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron 2012; 75:633-647. 
17.Wachtel H. Dysbalance of neuronal second messenger function in the aetiology of affective disorders: A pathophysiological concept hypothesising defects beyond first messenger receptors. J Neural Transm 1989; 75:21-29.