T‐2 toxin downregulates LHCGR expression, steroidogenesis, and cAMP level in human cumulus granulosa cells

Abstract

Our goals were to investigate whether environmentally relevant doses of T‐2 toxin can affect human ovarian granulosa cells' function and to reveal the potential mechanism of T‐2 toxin's action. Results showed that T‐2 toxin strongly attenuated luteinizing hormone/choriogonadotropin receptor (LHCGR) mRNA expression in follicle‐stimulating hormone (FSH)‐stimulated human cumulus granulosa cells. Addition of human chorionic gonadotropin was not able to elicit maximal response of ovulatory genes amphiregulin, epiregulin, and progesterone receptor. T‐2 toxin reduced mRNA levels of CYP19A1 and steroidogenic acute regulatory protein (STAR) and lowered FSH‐stimulated estradiol and progesterone production. Mechanistic experiments demonstrated that T‐2 toxin decreased FSH‐stimulated cyclic adenosine monophosphate (cAMP) production. Addition of total PDE inhibitor 3‐isobutyl‐1‐methylxanthine prevented T‐2 toxin's action on LHCGR, STAR, and CYP19A1 mRNA expression in FSH‐stimulated human cumulus granulosa cells. Furthermore, T‐2 toxin partially decreased 8‐bromoadenosine 3′5′‐cyclic monophosphate (8‐Br‐cAMP)‐stimulated LHCGR and STAR, but did not affect 8‐Br‐cAMP‐stimulated CYP19A1 mRNA expression in human cumulus granulosa cells. Overall, our data indicate that environmentally relevant dose of T‐2 toxin decreases steroidogenesis and ovulatory potency in human cumulus granulosa cells probably through activation of PDE, thus posing a significant risk for female fertility.

Glycolysis and Reactive Oxygen Species Production Participate in T-2 Toxin-Stimulated Chicken Heterophil Extracellular Traps

“…T-2 is the most toxic type A trichothecene mycotoxin, and the ubiquitous presence of T-2 in the natural environment has been reported to be a risk factor for cereals, animals, and humans . T-2 has toxin effects on neuronal cells, intestinal cells, and ovarian granulosa cells . Reports have proved that T-2 was primarily localized within the phagocytic elements of the duodenal lamina propria, especially neutrophils, and it also potentiated neutrophil counts in the lungs of mice when mice were given T-2. , Heterophils are phagocytic cells that have a wide range of antimicrobial activity, and heterophils release HETs to form the first line of the innate immune response against invading microbial pathogens in chickens. , In addition to the well-known protective role in the innate immune system, ET overproduction also has potentially harmful effects .…”

Review of the Reproductive Toxicity of T-2 Toxin

“…The antisteroidogenic effect of T-2 toxin was also observed in human cumulus GCs. Furthermore, T-2 toxin exposure decreased the expression of the ovulatory genes amphiregulin, epiregulin, and P receptor in human cumulus GCs, confirming that T-2 toxin has an antiovulatory effect . T-2 toxin exposure induced oxidative stress in porcine GCs by increasing the ROS content and reducing the activities of SOD and GSH-Px .…”

“…Furthermore, T-2 toxin exposure decreased the expression of the ovulatory genes amphiregulin, epiregulin, and P receptor in human cumulus GCs, confirming that T-2 toxin has an antiovulatory effect. 51 T-2 toxin exposure induced oxidative stress in porcine GCs by increasing the ROS content and reducing the activities of SOD and GSH-Px. 52 Wu et al reported that treatment with T-2 toxin leads to rat ovarian GC apoptosis caused by oxidative stress.…”

Impact of In Vitro Long-Term Low-Level DEHP Exposure on Gene Expression Profile in Human Granulosa Cells

“…The study was approved by the Ethics Committee of the Clinical Center of Vojvodina (approval number: 00-313), and signed informed consent was obtained from each participant. The exclusion criteria and the protocol for obtaining and isolating granulosa cells are described in [ 23 ].…”