Atrazine suppresses FSH-induced steroidogenesis and LH-dependent expression of ovulatory genes through PDE-cAMP signaling pathway in human cumulus granulosa cells

Pogrmić-Majkić, Kristina; Samardzija, Dragana; Stojkov-Mimic, Natasa J.; Vukosavljević, Jelena; Trninić-Pjević, Aleksandra; Kopitović, Vesna; Andrić, Nebojša

doi:10.1016/j.mce.2017.08.015

Cited by 42 publications

(17 citation statements)

References 52 publications

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“…Human cumulus granulosa cells were pretreated with the general, nonselective pharmacological inhibitor of PDEs IBMX. IBMX concentration was chosen based on the available literature data and our previous work . After pretreatment with the IBMX, the cells were treated with FSH or 10 nM T‐2 toxin for 48 hours.…”

Section: Resultsmentioning

confidence: 99%

“…Our results show that T‐2 toxin exposure decreased the FSH‐stimulated LHCGR mRNA level in the cells. The FHS‐stimulated LHCGR expression in granulosa cells is often target of other endocrine disruptors such as atrazine . The effect on LHCGR is critical for ovulatory response as inadequate acquisition of LHCGR in 10 nM T‐2 toxin‐exposed human granulosa cells renders hCG ineffective to support the expression of the ovulatory genes AREG , EREG , and PGR .…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to the FSH‐stimulated cells, where T‐2 toxin strongly decreased the LHCGR , STAR , and CYP19A1 mRNA expression to the control level, in 8‐Br‐cAMP‐stimulated cells this mycotoxin caused only partial reduction in the expression of LHCGR and STAR , while it did not affect the CYP19A1 mRNA expression. Similar to the T‐2 toxin's action, exposure of human granulosa cells to herbicide atrazine increases PDE activity and disrupts steroidogenesis and the ovulatory response . Several isoforms of PDE are detected in cultured granulosa cells, such as PDE4, PDE7, and PDE8.…”

Section: Discussionmentioning

confidence: 99%

“…This is the first study to reveal the effects and the possible mechanism disruptors such as atrazine. 28,30,31 The effect on LHCGR is critical for ovulatory response as inadequate acquisition of LHCGR in 10 nM T-2 toxin-exposed human granulosa cells renders hCG ineffective to support the expression of the ovulatory genes AREG, EREG, and PGR.…”

Section: Discussionmentioning

confidence: 99%

“…Different superscript letters indicate statistically significant differences between the treatment groups (P < .05) chosen based on the available literature data 27 and our previous work. 24,28 After pretreatment with the IBMX, the cells were treated with FSH or 10 nM T-2 toxin for 48 hours. Addition of IBMX prevented T-2 toxin's inhibitory action on the FSH-stimulated LHCGR (P < .013) ( Figure 7A), STAR (P < .046) ( Figure 7B), and CYP19A1…”

Section: T-2 Toxin Decreases Estradiol and Progesterone Production mentioning

confidence: 99%

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

Pogrmić-Majkić

Nenadov

Stanić

et al. 2019

Environmental Toxicology

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: T-2 Toxin Decreases Estradiol and Progesterone Production mentioning

confidence: 99%

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

Pogrmić-Majkić

Nenadov

Stanić

et al. 2019

Environmental Toxicology

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Environmental mixture with estrogenic activity increases Hsd3b1 expression through estrogen receptors in immature rat granulosa cells

Nenadov

Pogrmić-Majkić

et al. 2018

J of Applied Toxicology

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Humans are exposed not only to single endocrine disruptors, but also to chemical mixtures that can adversely affect their reproductive health. Steroidogenesis in reproductive tissues is emerging as the key target of endocrine disruptor action. Here, we analyzed the effect of environmental chemical mixtures with estrogenic activity on steroidogenic processes in immature rat granulosa cells and whether the observed steroidogenic effects were mediated through estrogen receptors. Extracts from untreated wastewater were prepared by solid-phase extraction and silica gel fractionation. ER-CALUX assay showed that the polar fractions of wastewater exerted different levels of estrogenic activity. Exposure of immature granulosa cells to the polar fraction exerting 9 ng of 17β-estradiol equivalents per liter of water of estrogenic activity increased mRNA expression of the key enzymes of progesterone biosynthetic pathway Star and Hsd3b1, but did not alter the level of Cyp19a1 and Lhr. Addition of estrogen receptor inhibitor ICI 182 780 prevented the estrogenic mixture-induced increase in Hsd3b1, but not Star mRNA level in immature granulosa cells. These results indicate that the environmental chemical mixtures with estrogenic activity exert endocrine disrupting effects by augmenting the progesterone biosynthetic pathway in immature rat granulosa cells, which is an effect achieved in part through activation of the estrogen receptors.

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Environmental Endocrinology

et al. 2022

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Atrazine suppresses FSH-induced steroidogenesis and LH-dependent expression of ovulatory genes through PDE-cAMP signaling pathway in human cumulus granulosa cells

Cited by 42 publications

References 52 publications

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

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

Environmental mixture with estrogenic activity increases Hsd3b1 expression through estrogen receptors in immature rat granulosa cells

Environmental Endocrinology

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