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.