Triazole fungicides induce adipogenesis and repress osteoblastogenesis in zebrafish

Abstract

Triazoles are a major group of azole fungicides commonly used in agriculture, veterinary, and human medicine. Maternal exposure to certain triazole anti-fungal medication causes congenital malformations, including skeletal malformations. We hypothesized that triazoles used as pesticides in agriculture also pose a risk of causing skeletal malformations in developing embryos. In this study, teratogenic effects of three commonly used triazoles, cyproconazole, paclobutrazol, and triadimenol, were investigated in zebrafish, Danio rerio. Exposure to the triazole fungicides caused bone and cartilage malformations in developing zebrafish larvae. Data from whole-embryo transcriptomics with cyproconazole suggested that exposure to this compound induces adipogenesis while repressing skeletal development. Confirming this finding, the expression of selected bone and cartilage marker genes were significantly downregulated with triazoles exposure as determined by quantitative PCR. The expression of selected adipogenic genes was upregulated by the triazoles. Furthermore, exposure to each of the three triazoles induced adipogenesis and lipid accumulation in vitro in 3T3-L1 pre-adipocyte cells. In vivo in zebrafish larvae, cyproconazole exposure caused lipid accumulation. These results suggest that exposure to triazoles promotes adipogenesis at the expense of skeletal development, and thus they expand the chemical group of bona fide bone to fat switchers.

A realistic mixture of ubiquitous persistent organic pollutants affects bone and cartilage development in zebrafish by interaction with nuclear receptor signaling

“…Agonists for the Vdr (calcitriol) or Rar (retinoic acid) were used as reference compounds and their chemical similarities were computed to all compounds in the POP mix. In addition, 4 triazole fungicides with a potential to be endocrine disruptors and posing serious concerns were chosen to complete the analysis: flusilazole, triadimenol, diniconazole and hexaconazole [52][53][54][55][56][57][58][59]. Hierarchical agglomerative nesting clustering was performed using the chemical fingerprints (toxprints) of all these compounds (Fig 7).…”

Ipconazole Induces Oxidative Stress, Cell Death, and Proinflammation in SH-SY5Y Cells

“…The widespread use of triazoles has allowed their accumulation in the environment in substantial amounts, and they are causing adverse effects in non-target organisms, posing a great risk to environmental and human health [ 7 ]. It has been experimentally demonstrated that triazoles can reduce skeletal formation in developing zebrafish, promoting bone malformations [ 8 ]. In mammals, in an ex vivo study it was observed that the murine heart is sensitive to the triazole tebuconazole, which was able to induce cardiac arrhythmia and cardiac electrical remodeling by blocking calcium and potassium currents; both effects produced by tebuconazole represent a potential risk to mammalian cardiac function [ 9 ].…”