Parental exposure to acrylamide disrupts sphingolipid metabolism and impairs transgenerational neurodevelopment in zebrafish (Danio rerio) offspring.

Acrylamide exposure has become an emerging environmental and food safety issue, and its toxicity poses a potential threat to public health worldwide. However, limited studies have paid attention to the detrimental effects of parental exposure to acrylamide on the neurodevelopment in zebrafish offspring. In this study, the embryos were life-cycle exposed to acrylamide (0.125 and 0.25 mM) for 180 days. Subsequently, these zebrafish (F0) were allowed to mate, and their offspring (F1) were collected to culture in clean water from embryos to adults. We employed developmental and morphological observations, behavioral profiles, metabolomics analyses, and transcriptional level examinations to investigate the transgenerational neurotoxicity with parental exposure to acrylamide. Our results showed that parental exposure to acrylamide harms the birth, development, and behavior characterization of the F1 zebrafish larvae, including poor egg quality, increased mortality rates, abnormal heart rates, slowed swimming activity, and heightened anxiety behavior, and continuously disturbs mental health in F1 adult zebrafish. The transcriptional analysis showed that parental chronic exposure to acrylamide deteriorates the neurodevelopment in F1 larvae. In addition, metabolomics analyses revealed that sphingolipid metabolism disruption may be associated with the observed abnormal development and behavioral response in unexposed F1 offspring. Overall, the present study provides pioneer evidence that acrylamide induces transgenerational neurotoxicity via targeting and disrupting sphingolipid metabolism, which reveals intergenerational transmission of acrylamide exposure and unravels its spatiotemporal toxicological effect on neurodevelopment.

Intergenerational toxic effects of parental exposure to bisphenol AF on offspring and epigenetic modulations in zebrafish.

Bisphenol AF (BPAF), an endocrine-disrupting chemical, has been detected in various environmental media because of its wide industrial applications. Meanwhile, substances that are known to be toxic to the reproductive system have been observed to interfere with the development of the offspring following parental exposure. This study was aimed at determining the gender-dependent intergenerational effects of BPAF on offspring development following either paternal or maternal exposure of adult zebrafish to an environmental concentration of BPAF. Four-month-old zebrafish (F0) were exposed to 10 µg/L of BPAF for 28 days, the developmental endpoints of F1 embryos were then tested without further treatment with BPAF. The results show that paternal BPAF exposure decreased the hatching rate, increased mortality, and shortened the body lengths of F1 larval offspring. In addition, it changed DNA and m6A RNA methylation gene expression levels in F0 testes and F1 larvae. Although maternal exposure increased mortality and enhanced antioxidant enzyme activities in F1 larvae, only DNA methylation gene expression was altered in F0 ovaries and F1 larvae. In addition, a short term BPAF exposure of zebrafish embryos from 4 h post-fertilization (hpf) until 120 hpf similarly impaired the early development of the larvae but only at a level relatively higher than 10 µg/L; and DNA and RNA methylation gene expression was regulated to some extent in BPAF exposure groups. Overall, our results indicate the gender-specific effects of BPAF on offspring development and epigenetic modulations, suggesting a relatively high susceptibility within the exposure window during gametogenesis and early embryonic developmental stages to environmental chemicals.

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle.

Rationale: Skeletal muscle insulin resistance is detectable before type 2 diabetes is diagnosed. Exposure to di(2-ethylhexyl) phthalate (DEHP), a typical environmental endocrine-disrupting chemical, is a novel risk factor for insulin resistance and type 2 diabetes. This study aimed to explore insulin signaling regulatory pathway in skeletal muscle of the DEHP-induced insulin-resistant mice and to investigate potential therapeutic strategies for treating insulin resistance. Methods: C57BL/6J male mice were exposed to 2 mg/kg/day DEHP for 15 weeks. Whole-body glucose homeostasis, oxidative stress and deregulated miRNA-mediated molecular transduction in skeletal muscle were examined. microRNA (miRNA) interventions based on lentiviruses and adeno-associated viruses 9 (AAV9) were performed. Results: Dnmt3a-dependent promoter methylation and lncRNA Malat1-related sponge functions cooperatively downregulated miR-17 in DEHP-exposed skeletal muscle cells. DEHP suppressed miR-17 to disrupt the Keap1-Nrf2 redox system and to activate oxidative stress-responsive Txnip in skeletal muscle. Oxidative stress upregulated miR-200a, which directly targets the 3'UTR of Insr and Irs1, leading to hindered insulin signaling and impaired insulin-dependent glucose uptake in skeletal muscle, ultimately promoting the development of insulin resistance. AAV9-induced overexpression of miR-17 and lentivirus-mediated silencing of miR-200a in skeletal muscle ameliorated whole-body insulin resistance in DEHP-exposed mice. Conclusions: The miR-17/Keap1-Nrf2/miR-200a axis contributed to DEHP-induced insulin resistance. miR-17 is a positive regulator, whereas miR-200a is a negative regulator of insulin signaling in skeletal muscle, and both miRNAs have the potential to become therapeutic targets for preventing and treating insulin resistance or type 2 diabetes.