Cadmium chloride-induced transgenerational neurotoxicity in zebrafish development
Introduction
Manufacturing and industrial processes are adding synthetic compounds to the air, water, and other natural ecosystems at an increasing rate (Wong et al., 2019). The accumulation of these compounds in the environment can harm the health of organisms, including that of humans. These compounds can also accumulate at higher levels of the food chain, ultimately damaging the physiology and altering the behavior of higher organisms (Martinelli et al., 2013). Cadmium is a heavy metal and a nonessential element that is often used for dyeing clothes, making synthetic fibers and paper, printing photographs, and in plastic manufacturing (Bernhoft, 2013; Mubeena et al., 2019). Cadmium can enter the aquatic environment through different methods, including dumping, rinsing, drainage, rainfall, and surface runoff (Muntau and Baudo, 1992). Recent studies have found that the concentration of cadmium in water can reach 0.1–0.3 μg/L, and that it can reach 30 μg/L in the wastewater outlets of some factories (Ahmed and Mokhtar, 2020; Malakahmad et al., 2011).
In organisms, the half-life of cadmium can reach 30–70 years, and it can cause immense tissue and organ damage (Suwazono et al., 2009). Studies have found that cadmium can be detected in most organs in the body, especially in the liver and intestine, and in plasma and urine (Swiergosz-Kowalewska, 2001), which in turn affects the cardiovascular system and causes brain damage (Satarug, 2012). Cadmium can also disrupt the thyroid system in rats, thereby reducing the secretion of thyroid hormones (Aleksandra et al., 2018). In lizards, cadmium increased the apoptosis of pituitary cells and damaged the structure of glial cells in the brain, thereby affecting brain development (Favorito et al., 2017; Ferrandino et al., 2009). In mammals, cadmium caused changes to testicular and ovarian tissue. In vitro experiments revealed that cadmium can significantly reduce sperm motility and fertilization rate, and can affect embryonic development (Zhao et al., 2017). Other studies reported that exposure to cadmium can affect cognitive and skeletal development in mammals (Lester et al., 1982; Bhattacharyya et al., 1988). Thus, excessive exposure to cadmium can affect many physiological processes.
Zebrafish (Danio rerio) are an excellent biomedical model organism that is recommended for experimental used in toxicological assessments (Li et al., 2020). Many research groups have studied cadmium toxicology in zebrafish (Renieri et al., 2017; Monaco et al., 2016). Cadmium has been shown to affect zebrafish metabolism, cardiovascular, behavior, nerves, and many other physiological processes (Cheng et al., 2000; Cambier et al., 2011). It also caused developmental toxicological effects and reduced the activity levels of zebrafish larvae and led to the decreased expression of nrxn2aa and nrxn2ab, genes that are important for neuronal development (Anon, 2017). Treatment with cadmium chloride resulted in significantly increased production of reactive oxygen species (ROS), which can disrupt the stability of the lipid bilayers of the cell membrane, and affect the heart and blood vessels (Cheng et al., 2001). Cadmium can also affect the brain structure by increasing neuronal apoptosis via the mitochondrial pathway (Yuan et al., 2015). Acute treatment of adult zebrafish with a high concentration of cadmium chloride can cause changes in ovarian structure, leading to developmental malformations in the F1 generation (Siekierska and Urbańska-Jasik, 2002), but to our knowledge, previous studies have not reported whether a low concentration treatment of adult zebrafish with cadmium chloride affects the behavior and neurotransmitter levels in the F1 offspring.
Behavior is a relatively sensitive indicator of internal physiological changes, even if the external morphology has remained unchanged. Changes in behavior often occur due to disrupted neurotransmitter secretion and neurodevelopmental damage in response to environmental toxins (Gattermann and Schreiner, 1986). The acute treatment of adult zebrafish and larvae fish with cadmium chloride can also disrupt behaviors, reduce swimming speed and swimming distance, and reduce the ability to respond to external stimuli (Monaco et al., 2016; Tian et al., 2020). However, the effects of cadmium on the behavior of offspring and neurotransmitters after treatment of parent fish have not been reported yet. In the present study, after adult zebrafish were treated with different concentrations of cadmium chloride, the F1 offspring were examined for changes in behavior, neurotransmitter levels, and expression of neurodevelopment-related genes to assess the toxicity of cadmium chloride with respect to the offspring of exposed individuals. The results provide a baseline environmental ecotoxicological assessment of cadmium chloride.
Section snippets
Zebrafish
All procedures were approved by the Fudan University Animal Care and Use Committee and were performed per governmental regulations in China. Adult AB zebrafish were housed in a circulating water system at a constant temperature of 28 °C, with a cycle of 14 h light and 10 h dark, and fed three times per day. Zebrafish were housed in male–female pairs and mated within one day. The embryos were collected maintained in embryo culture medium, at 28 °C (14-h/10-h light/dark). The protocols used for
Autonomous behavior of F1 offspring
The F1 offspring of parents exposed to concentration of 0.01 μM/L cadmium, showed no significant difference in behavior with respect to those originating from parents not exposed to cadmium (Fig. 1A). However, in the F1 generation of parents exposed to 0.1 and 1 μM/L cadmium chloride, the swimming distance was significantly reduced (p < 0.05; p < 0.01); this included the cumulative swimming distance as well as the total swimming distance (Fig. 1B, 1C). Compared with offspring of the non-exposed
Discussion
Many environmental pollutants can transfer toxicity to the next generation through the germline. In the present study, parental exposure to cadmium chloride significantly affected autonomous behavior and activity during the light–dark transition of zebrafish offspring, and affected the secretion of certain neurotransmitters and the expression of genes related to neuronal development. These changes were evidence of developmental neurotoxic damage in the offspring resulting from cadmium chloride
Conclusion
Parental exposure to cadmium chloride significantly reduced the swimming speed and distance covered by the F1 generation zebrafish; reduced the levels of neurotransmitters such as dopamine, serotonin, and AChE in offspring; disrupted neurotransmitter metabolism; and deregulated the expression of genes related to neuronal development, thereby inducing developmental neurotoxicity in the F1 generation.
Author contributions
Lianqun Zhou and Huancai Yin designed the experiments, Jingjing Tian and Jia Hu performed most of the experiments. Di Liu culture the zebrafish, Jingjing Tian, Jian Yin and Mingli Chen did data collection and informatics analysis. Jian Hu Lianqun Zhou and Huancai Yin analyzed the data and wrote the manuscript. Lianqun Zhou and Huancai Yin supervised the study. All authors have approved the final article.
CRediT authorship contribution statement
Jingjing Tian: . Jia Hu: . Di Liu: . Jian Yin: Software. Mingli Chen: Software. Lianqun Zhou: Conceptualization. Huancai Yin: Conceptualization.
Declaration of Competing Interest
All authors declare no conflicts of interest.
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (21876198), Science and technology project of Suzhou (sys2018101).
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These authors contributed equally.