*Review* **Bioactive Metabolites and Potential Mycotoxins Produced by** *Cordyceps* **Fungi: A Review of Safety**

**Bo Chen 1,2, Yanlei Sun 1,2, Feifei Luo <sup>1</sup> and Chengshu Wang 1,2,3,\***


Received: 30 May 2020; Accepted: 15 June 2020; Published: 19 June 2020

**Abstract:** Ascomycete *Cordyceps* fungi such as *C. militaris*, *C. cicadae*, and *C. guangdongensis* have been mass produced on artificial media either as food supplements or health additives while the byproducts of culture substrates are largely used as animal feed. The safety concerns associated with the daily consumption of *Cordyceps* fungi or related products are still being debated. On the one hand, the known compounds from these fungi such as adenosine analogs cordycepin and pentostatin have demonstrated different beneficial or pharmaceutical activities but also dose-dependent cytotoxicities, neurological toxicities and or toxicological effects in humans and animals. On the other hand, the possibility of mycotoxin production by *Cordyceps* fungi has not been completely ruled out. In contrast to a few metabolites identified, an array of biosynthetic gene clusters (BGCs) are encoded in each genome of these fungi with the potential to produce a plethora of as yet unknown secondary metabolites. Conservation analysis of BGCs suggests that mycotoxin analogs of PR-toxin and trichothecenes might be produced by *Cordyceps* fungi. Future elucidation of the compounds produced by these functionally unknown BGCs, and in-depth assessments of metabolite bioactivity and chemical safety, will not only facilitate the safe use of *Cordyceps* fungi as human food or alternative medicine, but will also benefit the use of mass production byproducts as animal feed. To corroborate the long record of use as a traditional medicine, future efforts will also benefit the exploration of *Cordyceps* fungi for pharmaceutical purposes.

**Keywords:** *Cordyceps* fungi; mass production; mycotoxins; biosynthetic gene cluster; toxicity; safety

**Key Contribution:** A few species of *Cordyceps* fungi have been used as traditional medicines for a long time. These fungi can now be mass-produced at magnitudes from dozens to thousands of tons a year in Asian countries. Based on the known compounds and putative mycotoxins that might be produced by these fungi; safety assessments and future efforts are still required to alleviate concerns when consuming these fungi as food supplements or health additives and using the related byproducts as animal feed.
