1. Introduction
Phthalates, e.g., di-2-ethylhexyl phthalate (DEHP), are widely used as plasticizers and they were detected in environments and also human tissues with various health impacts (Ma et al., 2022; Wang et al., 2022b; Zhao et al., 2022). Di(2-ethylhexyl) terephthalate (DEHTP), as a substitutive plasticizer, is increasingly used in toys, food packing materials and even medical devices (Bernard et al., 2023; Lessmann et al., 2019). Consequently, DEHTP and its metabolites were detected in environmental matrices such as sediments at μg/kg levels (Bulbul et al., 2022) and also in human urine samples at μg/L levels (Bernard et al., 2023; Lessmann et al., 2019; Schwedler et al., 2020). Accordingly, the effects of DEHTP on living organisms need further investigation to fully demonstrate its hazards.
Reproductive toxicities of phthalates had been widely reported on both humans and model organisms (Sedha et al., 2021; Sree et al., 2023). Notably, the reproduction processes involve embryo and germline development to connect adjacent generations (Wang et al., 2023). Accordingly, the long-term influences of phthalates earned special attentions. On one hand, the long-term influences of DEHP (one traditional phthalate) were recently explored with particular attentions on the hazards over generations. For example, parental or maternal exposure to DEHP resulted in obesogenic outcomes in offspring of drosophila (Chen et al., 2019) and behavior disorder and reproductive dysfunction in mice (Quinnies et al., 2015; Rattan et al., 2018). Moreover, the disturbances of DEHP on liver functions lasted over three generations in mice (Wen et al., 2020). On the other hand, the substitutive DEHTP can transfer over generations (Pacyga et al., 2023). Both the reproductive and generational effects demonstrated the impacts of plasticizers on the fitness which is important in sustaining ecological stability (Yue et al., 2021). Accordingly, the long-term effects of DEHTP are urging comprehensive studies and mechanism exploration.
Lipid metabolism provides energy for reproduction that connects generations. As expected, lipid metabolism disorder was employed to explain the multigenerational reproductive toxicities of environmental pollutants such as ionic liquids (Zhang et al., 2022). It was reported that phthalates disturbed lipid metabolism in Daphnia magna, with impacts on reproduction, development and lifespan (Seyourm and Pradhan, 2019) and they also impacted lipid metabolism in the dolphin (Xie et al., 2023). Therefore, DEHTP is assumed to provoke long-term exposure over generations, including lipid metabolism disorder. However, such an assumption needs support by empirical evidences.
Neural signals, e.g., dopamine (DA), acetylcholine (ACh), acetylcholinesterase (AChE), γ-aminobutyric acid (GABA) and serotonin (5-HT), are also essential for the behavior and reproduction (Liu et al., 2013). Moreover, it is also well connected with changes in lipid metabolism (Luo et al., 2022; Magnan et al., 2015). The stimulation on DA and inhibition on 5-HT reduced fat accumulation and metabolic dysfunction (Ali and Mirza, 2021; Crane et al., 2015). Meanwhile, the disturbance of antibiotics on the neural signals significantly inhibited satiety to induce fat accumulation (Luo et al., 2022). Lipid metabolism signals can also trigger neural regulations (Hamilton et al., 2015; Magnan et al., 2015). Therefore, investigations combining both neural signals and lipid metabolism are expected to provide more information regarding the toxicity mechanisms of DEHTP.
The purpose of the present study was to analyze the multi-generational toxicities of DEHTP on Caenorhabditis elegans . Moreover, lipid metabolism and neural regulations were explored to explain the multi-generational toxicities. We hypothesized that the multigenerational effects of DEHTP involved with both lipid metabolism and neural regulations. The findings not only confirmed such hypothesis and also showed oscillatory patterns in the effects over generations. The environmental hazards of plasticizer substitutes are indeed of concern, and further investigation is still needed to explore both impacts and underlying mechanisms.