Stage-dependent abnormalities induced by the fungicide triadimefon in the mouse.

Aim of this work is the study of abnormalities induced by the triazole triadimefon (FON) administered to pregnant mice at E8, E9, E10, E11 or E12. Pregnant CD-1 mouse were gavaged with FON 500 mg/kg at the selected stages and sacrificed at term and fetuses morphologically examined and processed for visceral and skeletal analysis. Administration of FON on E8, E10-E12 resulted in fetuses with cleft palate (E8 39% and E12 24% representing the peak of sensitivity, in E8 fetuses associated to severe skull basis abnormalities).

VPA-related axial skeletal defects and apoptosis: a proposed event cascade.

VPA axial malformations are related to embryonic somitic histone hyperacetylation. In cancer, histone hyperacetylation activates apoptosis. To verify if apoptosis is involved in somitic abnormalities, VPA-exposed embryos were evaluated for DNA fragmentation and for pro- (p53, acetylated p53, caspase 3) and anti-apoptotic (Sirt 1) protein expression.

The inhibition of embryonic histone deacetylases as the possible mechanism accounting for axial skeletal malformations induced by sodium salicylate.

In spite of the large use of salicylates, introduced into clinical practice more than 100 years ago, their anti-inflammatory and cancer preventive mechanisms are still under study. Teratogenic effects of salicylates have been reported in experimental animals since 1959 but the pathogenic pathways and the mechanisms of action were never described until now. The aim of this work is to verify if the inhibition of embryonic histone deacetylase (HDAC) enzymes and the consequent tissue hyperacetylation could be the mechanism responsible for axial skeletal defects described after the exposure of pregnant rodents to sodium salicylate (SAL).

Citral, an inhibitor of retinoic acid synthesis, attenuates the frequency and severity of branchial arch abnormalities induced by triazole-derivative fluconazole in rat embryos cultured in vitro.

The clinically used antimycotic fluconazole (fluco) is teratogenic in rodents. Exposure in vitro to fluco, other investigated azoles (triadimefon, triadimenol, flusilazole, ketoconazole and imazalil) or retinoic acid (RA), is correlated to branchial arch abnormalities. Inhibition of RA degradation has been suggested as the azole-related mechanism.

Relationship between embryonic histonic hyperacetylation and axial skeletal defects in mouse exposed to the three HDAC inhibitors apicidin, MS-275, and sodium butyrate.

Some histone deacetylase inhibitors (HDACi) have recently been related to teratogenic effects in rodents. Skeletal defects have been directly associated with embryonic hyperacetylation of somitic nuclei after valproic acid or trichostatin A exposure in vivo. Albeit the antitumoral activity of HDACi has been classically related to chromatin condensation due to histonic lysine hyperacetylation, nonhistonic proteins have also been suggested as an HDACi target.

Boric acid inhibits embryonic histone deacetylases: a suggested mechanism to explain boric acid-related teratogenicity.

Histone deacetylases (HDAC) control gene expression by changing histonic as well as non histonic protein conformation. HDAC inhibitors (HDACi) are considered to be among the most promising drugs for epigenetic treatment for cancer. Recently a strict relationship between histone hyperacetylation in specific tissues of mouse embryos exposed to two HDACi (valproic acid and trichostatin A) and specific axial skeleton malformations has been demonstrated.

Inhibition of histone deacetylase as a new mechanism of teratogenesis.

Histone deacetylases (HDACs) are nuclear and cytoplasmic enzymes that deacetylate a number of substrates, of which histones are the best known and described in the literature. HDACs are present in eukaryotic and bacteria cells, and are fundamental for a number of cellular functions, including correct gene expression. Surprisingly, only up to 20% of the whole genome is controlled by HDACs, but key processes for survival, proliferation, and differentiation have been strictly linked to HDAC enzyme functioning.

Antifungal triazole derivative triadimefon induces ectopic maxillary cartilage by altering the morphogenesis of the first branchial arch.

Background: The triazole derivative, triadimefon (FON), induces branchial arch abnormalities in post-implantation rat embryos cultured in vitro, and cranio-facial malformations in mouse fetuses. Ectopic maxillary cartilage has been also described as a typical FON-related malformation. This work studies the morphogenesis of the ectopic cartilage in rat embryos and fetuses exposed in vivo to FON during the early postimplantation period.

Postulated pathogenic pathway in triazole fungicide induced dysmorphogenic effects.

Triazole fungicides are used in medicine as well as in agricultural treatment of mycoses. The pharmacological mechanism is related to the inhibition of CYP enzymes involved in the formation of the fungal walls. A similar inhibition of human CYP enzymes has been suggested as the cause of triazole side effects in humans.

Inhibition of histone deacetylase activity on specific embryonic tissues as a new mechanism for teratogenicity.

Background: the inhibition of histone deacetylase (HDAC) has been reported as an effective mechanism on therapy in neoplastic diseases. Among HDAC inhibitors, Trichostatin A (TSA) and Valproic Acid (VPA) prevent the tumorigenesis in rodent and human models. Malformations as neural tube and axial skeletal defects are well-known VPA side effects.

Dysmorphogenic effects of some fungicides derived from the imidazole on rat embryos cultured in vitro.

Like triazole-derivatives, imidazole-derivatives exert their antifungal and toxicological properties by inhibiting P450 enzymes (Cyps). At the embryonic level, Cyp enzymes are involved also in the catabolism of the retinoic acid. Specific effects of triazole-derivatives have been reported on developing rodent embryos, and were correlated to an imbalance of the retinoid homeostasis.

Craniofacial and axial skeletal defects induced by the fungicide triadimefon in the mouse.

Background: Triadimefon is an antifungal derived from triazole. In in vitro whole-rodent embryo cultures, triazole-derivatives showed specific teratogenic effects at the branchial apparatus. The aim of the present work was to test in vivo triadimefon (FON), in order to verify a relationship between triazole exposure, embryonic abnormalities, and/or fetal malformations.

Effects of interleukin-12 administration during the pre- and peri-implantation period on mouse embryofetal development.

Problem: The immunological success of pregnancy is thought to depend upon the establishment of a balance between favorable and deleterious cytokines, the current paradigm viewing pregnancy as a T helper (Th)2 cytokine-dependent phenomenon. In this context, a particular attention should be directed to the potential role of interleukin (IL)-12, which promotes the development of Th1 responses, in the induction of adverse pregnancy-related phenomena. Indeed, very few data linked the Th1-inducer IL-12 to the event of abortion.

Effects of excess and deprivation of serotonin on in vitro neuronal differentiation.

The neurotransmitter serotonin (5HT) possesses developmental functions in vertebrates and invertebrates. Rodent embryos express 5HT receptors even before neural development, but the role of this neurochemical seems to be particularly important during axonal morphogenesis and differentiation and in neural crest cell migration. Moreover, 5HT inhibitors are teratogenic in mammals, inducing brain and heart abnormalities.

Pathogenic pathways in fluconazole-induced branchial arch malformations.

Background: A widely-used antimycotic agent, bis-triazole fluconazole (FLUCO), is able to produce abnormalities to the branchial apparatus (hypoplasia, agenesis, and fusion) in postimplantation rodent embryos cultured in vitro. The branchial apparatus is a complex and transient structure in vertebrate embryos and is essential for the development of the face skeleton. Branchial arch mesenchyme is formed by two different cellular populations: paraxial mesenchyme and ectomesenchyme, which originate from rhombencephalic neural crest cell (NCC) migration.

Comparative study of sodium valproate-induced skeletal malformations using single or double staining methods.

The teratogenic activity of xenobiotics is usually investigated by examining visceral and skeletal abnormalities of term fetuses. Although the rodent fetal skeleton is only partially ossified, the single stain for bone is the most commonly used method in routine teratology testing, while the double stain for evaluation of both bone and cartilage is often used only in basic research. The present work compares data obtained from rat fetuses using the two methods after exposure to the teratogenic agent sodium valproate at specific embryonic stages of development.