Di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) alters transcriptional profiles, lipid metabolism and behavior in zebrafish larvae

Abstract

Plasticizers are commonly used in different consumer goods and personal care products to provide flexibility, durability and elasticity to polymers. Due to their reported toxicity, the use of several plasticizers, including phthalates has been regulated and/or banned from the market. Di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) is an alternative plasticizer that was introduced to replace toxic plasticizers. Increasing global demand and lack of toxicity data and safety assessment of DINCH have raised the concern to human and animal health. Hence, in the present study, we investigated the adverse effects of DINCH (at concentrations ranging from 0.01 to 10 μM) in early developmental stages of zebrafish using different endpoints such as hatching rate, developmental abnormalities, lipid content, behavior analysis and gene expression. We found that DINCH caused hatching delay in a dose-dependent manner and altered the expression of genes involved in stress response. Lipid staining using Oil Red O stain showed a slight lipid accumulation around the yolk, brain, eye and neck with increasing concentration. Genes associated with lipid transport such as fatty acid synthesis, β-oxidation, elongation, lipid transport were significantly altered by DINCH. Genes involved in cholesterol biosynthesis and homeostasis were also affected by DINCH indicating possible developmental neurotoxicity. Behavioral analysis of larvae demonstrated a distinct locomotor activity upon exposure to DINCH. The present data shows that DINCH could induce physiological and metabolic toxicity to aquatic organisms. Hence, further analyses and environmental monitoring of DINCH should be conducted to determine its safety and toxicity levels.

Insights into the Endocrine Disrupting Activity of Emerging Non-Phthalate Alternate Plasticizers against Thyroid Hormone Receptor: A Structural Perspective

“…In addition, prenatal and lactational exposures of DINCH were associated with dysregulation of estrogen signaling gene expression in rat testes [ 64 ]. Exposure of DINCH in zebra fish caused hatching delays and disturbed the gene expression for stress response [ 65 ]. In addition, the exposure caused lipid accumulation in various parts of the body, affected the expression of genes for lipid transport and cholesterol biosynthesis, and impacted the locomotor activity of larvae.…”

Alternative Plasticizers As Emerging Global Environmental and Health Threat: Another Regrettable Substitution?

“…Higher levels of APs in the environment can lead to potential ecological and health risks. Generally, data relating to toxicities on emerging alternatives to phthalate plasticizers are extremely limited, however, some typical APs compounds, including acetyl tributyl citrate (ovarian toxicity, , endocrine disrupting and neurotoxicity), diisononyl cyclohexane-1,2 dicarboxylate (cytotoxicity, DNA damage, , neurotoxicity, metabolic toxicity), tris-2-ethylhexyl phosphate (endocrine disrupting , ), tricresyl phosphate (neurotoxicity, , DNA damage , ), triphenyl phosphate (reproductive toxicity, developmental toxicity, endocrine disrupting − ), and tris-2-ethylhexyl trimellitate (cell toxicity, estrogenic activity, hepatotoxicity) have potential toxic effects, which needs further exploration. Bis-2-ethylhexyl terephthalate was considered a safe alternative by a few researchers , in opposition to in silico investigations, while a Japanese study suspected it could be a potential endocrine disruptor and reproductive toxicant.…”

Cumulative Exposure to Phthalates and Their Alternatives and Associated Female Reproductive Health: Body Burdens, Adverse Outcomes, and Underlying Mechanisms

“…In recent years, several studies have focused on the effects of alternatives on oxidative stress. It was observed earlier that the level of expression of the cyc1 gene, which is involved in mitochondrial oxidative phosphorylation, and the fkbp4 gene, which has a protective effect against oxidative stress, was increased after exposure to DINCH. − Cong et al observed that all doses of DINCH exposure resulted in the downregulation of the sod1 , sod2 , and sod3 genes in zebrafish . A study found that the activity of the SOD1 enzyme was dose-dependent with DINCH in rats after in utero exposure on postnatal day 60 .…”