Azole Fungicides and Their Endocrine Disrupting Properties: Perspectives on Sex Hormone-Dependent Reproductive Development

Abstract

Azoles are antifungal agents used in both agriculture and medicine. They typically target the CYP51 enzyme in fungi and, by so doing, disrupt cell membrane integrity. However, azoles can also target various CYP enzymes in mammals, including humans, which can disrupt hormone synthesis and signaling. For instance, several azoles can inhibit enzymes of the steroidogenic pathway and disrupt steroid hormone biosynthesis. This is of particular concern during pregnancy, since sex hormones are integral to reproductive development. In other words, exposure to azole fungicides during fetal life can potentially lead to reproductive disease in the offspring. In addition, some azoles can act as androgen receptor antagonists, which can further add to the disrupting potential following exposure. When used as pharmaceuticals, systemic concentrations of the azole compounds can become significant as combatting fungal infections can be very challenging and require prolonged exposure to high doses. Although most medicinal azoles are tightly regulated and used as prescription drugs after consultations with medical professionals, some are sold as over-the-counter drugs. In this review, we discuss various azole fungicides known to disrupt steroid sex hormone biosynthesis or action with a focus on what potential consequences exposure during pregnancy can have on the life-long reproductive health of the offspring.

Resistance to Azole Drugs by Fungal Species Isolated from Date Palm Samples within Lafia Metropolis, Nigeria

“…Different azoles have varying affinities for their target, which can explain the variations in their range of effectiveness. This is evident in the resistance profiles of different fungi [17]. Other factors that affected the effectiveness of the test drugs and resistance by fungal isolates were the variations in the structure of azoles which determines the patterns of cross-resistance among species of the same genera [18,19], extensive use of an azole drug, and genetic mutation as noticed in the ERG11 gene.…”

Pesticides and Their Impairing Effects on Epithelial Barrier Integrity, Dysbiosis, Disruption of the AhR Signaling Pathway and Development of Immune-Mediated Inflammatory Diseases

“…Research to date has demonstrated that the toxic effects of pesticides are manifested in different ways, from acute and sublethal effects to severe intoxication by chronic exposure to low doses. Evidence from several studies (reviewed by [ 30 , 31 ]) supports carcinogenicity [ 32 , 33 , 34 ], neurotoxicity [ 35 , 36 , 37 , 38 , 39 ], endocrine and developmental disruption [ 40 , 41 , 42 , 43 , 44 , 45 ] and metabolic toxicity [ 46 , 47 , 48 ] as underlying pathogenic mechanisms of pesticides.…”

Potency of Hexaconazole to Disrupt Endocrine Function with Sex Hormone-Binding Globulin

“…In recent years, triazole fungicides have received a lot of attention due to reports that they may damage the endocrine system, including steroid hormones [ 6 , 7 ]. There are numerous potential mechanisms by which these fungicides could cause androgenic disruption [ 7 ].…”

“…In recent years, triazole fungicides have received a lot of attention due to reports that they may damage the endocrine system, including steroid hormones [ 6 , 7 ]. There are numerous potential mechanisms by which these fungicides could cause androgenic disruption [ 7 ]. Although many different pathways of triazole-induced endocrine-disrupting actions, such as oestrogen receptor and thyroid hormone receptor, have received attention, there is still a knowledge vacuum in these areas.…”