(-)-alpha-Zearalenol

Danger

H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P264, P264+P265, P270, P280, P301+P317, P301+P330+P331, P302+P352, P302+P361+P354, P304+P340, P305+P354+P338, P316, P317, P318, P319, P321, P330, P332+P317, P362+P364, P363, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Regulation (EC) No 178/2002 (amended)

Regulation (EC) No 178/2002 (amended)

Mycotoxins, such as alpha-zearalenol (alpha-ZOL) and beta-zearalenol (beta-ZOL), as contaminants of animal food can impair fertility and can cause abnormal fetal development in farm animals. The addition of alpha- or beta-ZOL (7.5, 15 and 30 microM) to cultures stimulated with FSH (0.01 microg) or forskolin (10 microM) reduced progesterone synthesis and the levels of p450scc and 3beta-HSD transcripts in a dose-dependent manner (P<0.05). The enzymatic activity of 3beta-HSD and the abundance of p450scc protein were also reduced by these mycotoxins. The effects of mycotoxins on FSH receptor-dependent and receptor-independent pathways indicate that adenylate cyclase activity and/or regulatory pathways further downstream are targets of mycotoxin actions. The apparent dose-dependent reduction of p450scc and 3beta-HSD transcripts implies an effect of alpha- and beta-ZOL on transcriptional regulation of these enzymes. Testing the zearalenone derivatives, _- and _-ZOL, which is metabolised in the liver, as an examination of excretory products indicated a predominance of the _ epimer in pig and man. (A15419) Generally, alpha-zearalenol possess estrogenic potencies that are approximately 50% compared to that of E2, and their order of estrogenic potency (in both in vitro receptor competitive binding and in vivo induction of Vtg and Zr-proteins levels) is: alpha-zearalenol > beta-zearalenol. It has also been observed that mycotoxin alpha and beta zearalenol influence the apoptosis and proliferation of cultured granulosa cells from equine ovaries. (L2099) The mechanisms by which _-ZOL or _-ZOL mediates their cytotoxic effects appear to differ according to cell type and the exposed toxins. In evaluating the toxicity of _-ZOL and _-ZOL on RAW264.7 macrophages, _-ZOL not only more strongly reduced the viability of cells than did _-ZOL, but it also induced cell death mainly by apoptosis rather than necrosis. The zearalenone metabolites induced loss of mitochondrial membrane potential (MMP), mitochondrial changes in Bcl-2 and Bax proteins, and cytoplasmic release of cytochrome c and apoptosis-inducing factor (AIF). Use of an inhibitor specific to c-Jun N-terminal kinase (JNK), p38 kinase or p53, but not pan-caspase or caspase-8, decreased the toxin-induced generation of reactive oxygen species (ROS) and also attenuated the _-ZOL- or _-ZOL-induced decrease of cell viability. The activation of p53, JNK or p38 kinase by zearalenone metabolites is the main upstream signal required for the mitochondrial alteration of Bcl-2/Bax signaling pathways and intracellular ROS generation, while MMP loss and nuclear translocation of AIF are the critical downstream events for zearalenone metabolite-mediated apoptosis in macrophages. (A15420)