Fungal species produce various secondary metabolites with carcinogenic and genotoxic properties, including aflatoxins, ochratoxins, fumonisins, sterigmatocystin, and griseofulvin. Acute or chronic exposure to these mycotoxins through contaminated food and feed can cause DNA damage, chromosomal instability, and epigenetic changes, ultimately leading to cancer. This review focuses on IARC-classified carcinogenic mycotoxins and their contribution to cancer development by disrupting the DNA damage response (DDR), thereby affecting apoptosis, cell cycle regulation, and genomic stability. Current knowledge of co-exposure to mycotoxins, host susceptibility, and validated biomarkers remains limited, particularly regarding the regulation of DDR genes. This necessitates more in-depth mechanistic and epidemiological research. Network analysis of host genes associated with mycotoxins in the CTD, integrated with DDR-related genes curated from CancerSEA, identified candidate DDR-associated genes implicated in pathways related to cell cycle regulation, DNA repair, oxidative stress response, and apoptosis. These findings represent database-derived associations and computational prioritization, rather than evidence of causal mechanistic roles in mycotoxin-induced carcinogenesis. Enrichment analysis using the Enrichr tool further identified the association between mycotoxin-associated DDR genes and cancer. In brief, this review enhances the understanding of the role of mycotoxins in DDR mechanisms and their potential contribution to cancer development, thereby providing a basis for improved molecular and translational approaches to address the associated health risks.
Two small peptides were purified from the venom of the vermivorous cone snail, Conus tessulatus, and evaluated for neuroactivity. Structural characterization by Edman sequencing and mass spectrometry revealed that the two peptides, named ts3b and ts3c, are 14 amino acids long and can be classified as mini-M conotoxins under framework III, M-superfamily, M2 branch. Native samples of ts3b and ts3c caused temporary swimming paralysis in fish, yet elicited distinct responses in the dorsal root ganglion (DRG) assay and the Constellation Pharmacology platform. Peptide ts3b caused mild sluggishness and shaking in young mice and irreversible, indirect excitation in a primary culture of DRG neurons. Furthermore, nanomolar concentration of native ts3b affected small diameter peptidergic nociceptors (PNs) and c-low threshold mechanoreceptors (C-LTMRs) in the DRG. Interestingly, ts3c caused an irreversible block in cultured DRG neurons, primarily affecting capsaicin-sensitive PN cells and capsaicin-insensitive non-peptidergic nociceptors (NPNs). The bioactivities suggest that ts3b and ts3c may target distinct ion channels or receptors. Two ts3b toxiforms were also identified as ts3b Asn15 toxiform and ts3b Ser7Arg, Asn15 toxiform. The toxiforms have a similar loop pattern, post-translational modifications, and cysteine framework with ts3b. Native ts3b and the toxiforms caused mild lethargy in mice. Peptide ts3b and ts3c are the first neuroactive mini-M conotoxins described from C. tessulatus. Few neuroactive conotoxins have been reported under the M-2 branch, and these compounds may have novel molecular and pharmacological targets due to their diverse structural conformations.
Tifton 68 (Cynodon nlemfuensis) is a cyanogenic forage grass that may also contribute to dietary sulfur exposure. Young Tifton 68 was introduced into a 32-animal dairy herd. Within approximately 2 days, neurological disease was recognized; eight cattle were affected and four died. Affected cattle developed visual and postural deficits, hypermetria, intention tremors, recumbency, and convulsions. The forage produced a rapid positive reaction in the qualitative sodium picrate paper test. Neuropathological examination of one cow revealed bilateral pseudolaminar cortical neuronal necrosis with selective deep gray-matter and cerebellar injury. The outbreak was strongly associated with Tifton 68, but cyanide exposure was not analytically confirmed and total sulfur exposure was not determined, leaving cyanide exposure and sulfur-associated polioencephalomalacia as competing etiological hypotheses.
