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PubMed1982

In vitro mycotoxin binding to bovine uterine steroid hormone receptors.

The mycotoxins, aflatoxin B(1), aflatoxin M(1), aflatoxicol and zearalenone were tested for binding to bovine endometrial estrogen and progestin receptors. Radioinert estradiol-17beta, estrone, testosterone, and cholesterol were evaluated for binding to the estrogen receptor. Zearalenone and aflatoxicol but not aflatoxins B(1) and M(1) competed with estradiol-17beta for the estrogen receptor. The order of binding affinities for the estrogen receptor were zearalenone > estradiol-17beta > estrone > aflatoxicol. The affinity of zearalenone for the estrogen receptor was 2-3 times that of estradiol-17beta. Progesterone, cortisol, radioinert R 5020, and cholesterol were evaluated for binding to the progestin receptor. None of the tested compounds except R 5020 and progesterone competed for the progestin receptor. The significance of aflatoxicol binding to the estrogen receptor is unclear. It is proposed that aflatoxicol binding to the receptor may alter gene expression in target tissues or act at the level of the hypothalamus to inhibit gonadotropin secretion and ovulation. These effects could explain reports of reduced fertility in domestic animals following ingestion of aflatoxin contaminated feedstuffs. It is also suggested that the mechanism of adverse effects on fertility of chronic aflatoxin ingestion in cattle and other livestock should be more thoroughly investigated.

Journal Article↗

PubMed1990

Apoptosis induced in macrophages and T blasts by the mycotoxin sporidesmin and protection by Zn2+ salts.

Incubation of 48 h concanavalin A stimulated spleen cells (T blasts) and murine peritoneal macrophages with the mycotoxin sporidesmin results in DNA fragmentation characteristic of apoptosis. Morphological changes, particularly condensed chromatin, observed following incubation of these cells with sporidesmin and the immunotoxin gliotoxin and related epipolythiodioxopiperazines (ETP) also show changes characteristic of apoptosis. The presence of Zn2+ salts in the culture medium at concentrations non toxic to the cells over the time period studied protects against DNA damage and morphological change. Interaction between Zn2+ and the reduced form of a simple ETP compound assessed by spectral changes demonstrated the formation of a weak complex between the two molecules. Complex formation between zinc and thiol however was insufficient to prevent oxidative damage to plasmid DNA in vitro by inhibiting auto-oxidation of the reduced ETP compound because of the looseness of the interaction. Cd2+, which appears to form a tighter complex with the dithiol does inhibit cleavage of plasmid DNA. These results establish that the toxicity of sporidesmin may be due in part to its ability to induce apoptosis or programmed cell death in sensitive cells. In addition the immunotoxin gliotoxin and related compounds have now been shown to induce the same characteristic morphological changes in cells of haemopoietic origin. The inhibition of apoptosis induced by ETP compounds by Zn2+ appears to be due to direct inhibition of apoptosis rather than Zn2+ acting as an antioxidant. These results demonstrate the inhibition of apoptosis induced by ETP compounds by Zn2+ and suggest an alternate explanation for the known prophylactic effect of Zn2+ on sporidesmin induced tissue damage.

Animals↗

PubMed1986

Metabolism and clearance of T-2 mycotoxin in perfused rat livers.

Isolated perfused rat livers were used to study the metabolism and clearance of T-2 mycotoxin, a nonprotein Fusarium metabolite known to cause illness or death on contact or by ingestion. To evaluate the in vitro hepatic metabolism, clearance, and rate of biliary excretion of T-2 toxin, [3H]T-2 toxin was delivered under constant perfusate flow (8 ml/min, 33.9 micrograms T-2/min) in a single-pass experiment. Steady-state conditions were achieved within 10 min as indicated by a constant exit rate of radiolabel in the effluent. At steady state, 93 +/- 4% of the delivered [3H]T-2 was extracted and metabolized by the liver, while 4.6 +/- 0.3% remained unmetabolized in the effluent perfusate. The excretion rate of metabolites and conjugates into bile was constant after a 10-min perfusion. Radioactivity measured in bile accounted for 55% of the total radiolabel delivered during the perfusion experiment (1 hr). T-2 toxin was metabolized and eliminated as 3'hydroxy HT-2, 3'hydroxy T-2 triol, 4-deacetylneosolaniol, T-2 tetraol, and glucuronide conjugates of HT-2, 3'hydroxy HT-2, and T-2 tetraol. Approximately 7% of the administered radiolabel remained in the liver and was identified as 4-deacetylneosolaniol (18%), T-2 tetraol (41%), and conjugated metabolites (41%). Total recovery of administered radiolabel associated with T-2 and its metabolites equaled 97.6% (bile, 52.5%; perfusate, 38.0%; liver, 7.1%). Approximately 3% of the biliary radiolabel was not identified. These studies describe the use of a perfused organ system to determine the rate of formation of T-2 metabolites and their elimination into bile.

Animals↗

PubMed1987

Risk assessment of the mycotoxin zearalenone.

Trans-zearalenone, a resorcylic acid lactone, also known as F-2 toxin, is a nonsteroidal estrogenic mycotoxin produced by numerous species of Fusarium. As a result zearalenone is found in a number of cereal crops and their derived food products. A closely related substance "zeranol" (zearalanol) is at present being used in the United States and Canada as an anabolic agent in beef cattle. Zearalenone has been implicated in numerous incidences of mycotoxicosis in farm animals, especially pigs. In this report the health risks to Canadians due to the presence of zearalenone in food products have been evaluated. The first part of the report deals with the physicochemical aspects, mycology, laboratory production, and natural occurrence in plant products and animal products of zearalenone. The stability of zearalenone in foods and feeds, the effects of food processing, and the removal from foods and feeds by physicochemical means are also discussed. From these data the daily exposure of Canadians to zearalenone from food consumption has been estimated to be in the range of 0.05-0.10 microgram/kg b.w./day (mean and 90th percentile of eaters, respectfully) for young children, the highest consumption group on a body weight basis. The second part of the report deals with the metabolic disposition of zearalenone as well as the available toxicity data base of zearalenone in laboratory animals, farm animals, and humans. Studies in various species (rodents, rabbits, pigs, monkeys) including man have shown that zearalenone has estrogenic and anabolic activity. Its major effects are on reproduction, including reproductive organs and their function, leading to hyperestrogenism. Zearalenone has been implicated in numerous incidences of hyperestrogenism in farm animals, especially pigs. For reproductive effects a no adverse effect level (NOAEL) of 0.06 mg/kg b.w./day was estimated for the pubertal pig, the most sensitive species tested. Important differences in the biotransformation of zearalenone were noted, with greater amounts of alpha-zearalenol, the more estrogenic metabolite, formed in man and the pig compared to rodents. In addition, the biological half-life of these substances was longer in man than in other species tested. The binding of zearalenone to estrogen receptors was approximately 20-fold lower than that seen with 17 beta-estradiol in several assays.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Isolation and structure determination of natural analogues of the mycotoxin ochratoxin A produced by Aspergillus ochraceus.

Three new natural mycotoxins, analogues of ochratoxin A, in which the phenylalanine moiety is replaced by serine, hydroxyproline or lysine, were isolated from cultures of Aspergillus ochraceus by TLC followed by HPLC column chromatography. Their structures were determined after acidic hydrolysis by the characterisation of both their amino acid moieties and of ochratoxin alpha, the chlorinated dihydroisocoumarin moiety of ochratoxin A. These structures were confirmed by mass spectrum analysis.

Aspergillus ochraceus↗

PubMed1984

A comparative study on cytotoxicities and biochemical properties of anthraquinone mycotoxins emodin and skyrin from Penicillium islandicum Sopp.

The anthraquinone mycotoxins emodin and skyrin were examined for the inhibitory effects on murine leukemia L1210 culture cells, oxidative phosphorylation of rat liver mitochondria, and Na+, K+-activated ATPase activity of rat brain microsomes to find the differences between their modes of toxic action. Skyrin exhibited a stronger inhibitory effect than emodin on the growth of L1210 culture cells. Emodin showed a stronger uncoupling effect than skyrin on mitochondrial respiration. Skyrin inhibited Na+, K+-activated ATPase activity of rat brain microsomes but emodin did not inhibit.

Animals↗

PubMed1987

Detection of the lethal effects of T-2 mycotoxin on cells using a rapid colorimetric viability assay.

A colorimetric method of determining cell viabilities in cultured cells is described. The system is based on the ability of mitochondrial enzymes in live but not dead cells to chemically reduce a tetrazolium salt (MTT) into a colored formazan dye which can be detected at 570 nm using a multiwell scanning spectrophotometer. 48 h Chinese hamster ovary (CHO) cell cultures are used in the assay and the amount of colored product formed is directly proportional to cell number over a range of 0.39-12.5 X 10(4) cells/ml. The cytotoxic effects of T-2 mycotoxin can also be detected colorimetrically using this method. The toxin dose which inhibits formazan formation (50% endpoint = 14-16 ng/ml) is very comparable to that which inhibits cell viability (17 ng/ml), or protein and DNA synthesis (10 ng/ml). This system also works well with mitogen-stimulated primary lymphocyte cultures but these cells exhibit a much more sensitive response to T-2 effects having a 50% inhibition endpoint of 2 ng/ml. The assay is rapid to perform and gives a high degree of precision and could serve as a valid alternative to viability assays currently in use.

Animals↗

PubMed1987

Metabolism of three trichothecene mycotoxins, T-2 toxin, diacetoxyscirpenol and deoxynivalenol, by bovine rumen microorganisms.

The three trichothecene mycotoxins T-2 toxin, diacetoxyscirpenol (DAS) and deoxynivalenol (DON) were incubated in vitro for 12, 24 and 48 h with rumen microorganisms obtained from a fistulated dairy cow. Gas chromatographic and gas chromatographic-mass spectrometric analyses of extracts indicated all three toxins were biotransformed to a variety of deepoxy and deacylated products. DON was partially converted to a product identified as deepoxy DON. DAS was rapidly converted to four products including 15-monoacetoxyscirpenol (MAS), scirpentriol and two new compounds identified as 15-acetoxy-3 alpha,4 beta-dihydroxytrichothec-9,12-diene (deepoxy MAS) and 3 alpha,4 beta,15-trihydroxytrichothec-9,12-diene (deepoxy scirpentriol). T-2 toxin was also completely biotransformed to the products HT-2, T-2 triol and two new metabolites identified as 15-acetoxy-3 alpha,4 beta-dihydroxy-8 alpha-(3-methylbutyryloxy) trichothec-9,12-diene (deepoxy HT-2) and 3 alpha,4 beta,15-trihydroxy-8 alpha-(3-methylbutyryloxy)trichothec-9,12-diene (deepoxy T-2 triol).

Animals↗

PubMed2006

Registration of T-2 mycotoxin with total internal reflection ellipsometry and QCM impedance methods.

A sensitive optical method of total internal reflection ellipsometry (TIRE) in conjunction with immune assay approach was exploited for the registration of T-2 mycotoxin in a wide range of concentrations from 100 microg/ml down to 0.15 ng/ml. Association constants of 1.4x10(6) and 1.9x10(7)mol(-1)s for poly- and monoclonal T-2 antibodies, respectively, were evaluated from TIRE kinetic measurements. According to TIRE data fitting, binding of T-2 molecules to antibodies (at saturation) has resulted in the increase in adsorbed layer thickness of 4-5 nm. The QCM impedance measurements data showed anomalously large mass increase and film softening, most likely, due to the binding of large T-2 aggregates to antibodies.

Biosensing Techniques↗

PubMed2006

Capillary electrophoresis of the mycotoxin zearalenone using cyclodextrin-enhanced fluorescence.

Certain of the cyclodextrins are capable of significantly enhancing the native fluorescence of the estrogenic mycotoxin zearalenone (ZEN). Twenty-two cyclodextrins (CDs) were screened for their ability to enhance the fluorescence of ZEN in a capillary electrophoresis-laser induced fluorescence (CE-LIF) format. Of the CDs that were examined heptakis (2,6-di-O-methyl)-beta-CD gave the greatest enhancement. The heptakis (2,6-di-O-methyl)-beta-CD was applied to the development of a CE-LIF method for detection of ZEN in maize. The resulting method was capable of detecting ZEN with a limit of quantitation of 5 ng/g maize. Recoveries of ZEN from maize spiked over the range from 5 ng/g to 500 ng/g averaged 103.1+/-8.5% (n=20). The CE-LIF method will be useful for future studies of ZEN in maize.

Cyclodextrins↗

PubMed2003

Increased expression of CD95-ligand and other apoptotic signaling factors by fumonisin B1, a hepatotoxic mycotoxin, in livers of mice lacking tumor necrosis factor alpha.

Fumonisin B1 (FB1), a mycotoxin, is a potent inhibitor of ceramide synthase, and produces organ-, species-, and even gender-specific toxic responses in animals. The hepatotoxic response of FB1 in mice involves accumulation of free sphingoid bases and induction of inflammatory cytokines including tumor necrosis factor alpha (TNFalpha). The FB1-induced hepatotoxic responses were reduced in mice lacking TNFalpha receptor (TNFR) 1 or TNFR2. However, the hepatotoxicity was exacerbated in mice lacking TNFalpha. We therefore investigated the modulation of various other apoptotic signaling factors in TNFalpha-knockout (TKO) mice compared to wild-type (WT) strain after repeated daily subcutaneous injections of 2.25 mg/kg FB1 treatment for 5 days. Expression of various signaling genes in liver was evaluated by ribonuclease protection assay. Expression of CD95-ligand (FasL) was more than doubled in TKO animals after FB1 whereas it was unaltered in the WT group. FB1 did not alter CD95 expression in either strain; however, expressions of TRAIL, and downstream signaling factors FADD, TRADD, and caspase 8 were higher in FB1-treated TKO mice than in the corresponding WT animals. The TKO strain had a higher constitutive expression of apoptotic factors except CD95L. In addition to the CD95 and TNFalpha systems, the expression of apoptotic molecules bcl-2, b-myc, c-myc, bax, max, mad and IL1alpha was induced by FB1 in TKO mice to a greater extent than in WT animals; many of these factors also had a higher constitutive expression in TKO animals than WT mice. Results indicated that FB1 can induce CD95 modulated signaling when TNFalpha is absent. Differential constitutive expression of apoptotic genes in TKO mice may explain their increased sensitivity to FB1. These results are important in characterizing the modulating effect of TNFalpha on apoptotic signaling and in explaining the unexpected sensitivity of mice lacking this cytokine in response to hepatotoxic xenobiotics.

Animals↗

PubMed2005

Applicability of an in vitro digestion model in assessing the bioaccessibility of mycotoxins from food.

Food is considered a major route of exposure to many contaminants. Only the fraction of the contaminant that is released from the food (bioaccessibility) and is bioavailable can exert toxic effects. Insufficient knowledge on the bioavailability may hamper an accurate risk assessment of ingested contaminants in humans. This paper describes the applicability of an in vitro digestion model allowing for measurement of the bioaccessibility of ingested mycotoxins from food as an indicator of oral bioavailability. Bioaccessibility of aflatoxin B(1) from peanut slurry and ochratoxin A from buckwheat was high, 94% and 100%, respectively, and could be determined reproducibly. With the in vitro digestion model, the bioaccessibilities of aflatoxin B(1) and ochratoxin A in the presence of four different absorption modulators were in five out of six situations in accordance with the in vivo effects in humans and animals. By determining the effect of chlorophyllin on the transport of aflatoxin B(1) across the intestinal Caco-2 cells, also the sixth combination was in agreement with data in humans. Hence, the in vitro digestion model, combined with Caco-2 cells, is a powerful experimental tool, which can aid to a more accurate risk assessment of ingested contaminants.

Aflatoxin B1↗

PubMed2005

Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells.

The mycotoxin alternariol (AOH) is found in food and beverages infected by Alternaria alternata. Because consumption of foodstuffs contaminated with A. alternata has been implicated in an elevated incidence of esophageal carcinogenesis, we have investigated the estrogenic potential, the effect on cell proliferation, and the genotoxic effect of AOH in cultured mammalian cells. AOH replaced E2 from isolated human estrogen receptors alpha and beta and increased the level of alkaline phosphatase (ALP) mRNA and the enzymatic activity of ALP in a human endometrial adenocarcinoma cell line (Ishikawa cells). The estrogenicity of AOH was about 0.01% of that of E2. The effects in Ishikawa cells were reversed by the ER antagonist ICI 182,780. Analysis of cell proliferation by flow cytometry and microscopy of Ishikawa and Chinese hamster V79 cells revealed that AOH inhibited cell proliferation by interference with the cell cycle. The genotoxic potential was assessed by the micronucleus (MN) assay and immunochemical differentiation between MN containing whole chromosomes (kinetochore-positive) and DNA fragments (kinetochore-negative) in Ishikawa and V79 cells. AOH induced kinetochore-negative MN in both cell lines. This is the first report on the estrogenic potential, inhibition of cell proliferation and clastogenicity of AOH in Ishikawa and V79 cells in vitro.

Adenocarcinoma↗

PubMed2006

Degradation of trichothecene mycotoxins by chicken intestinal microbes.

The degradation of 12 trichothecene mycotoxins by chicken intestinal microbes was monitored by liquid chromatography-ultraviolet-mass spectrometry under positive ion atmospheric pressure chemical ionization. Two pathways were observed: deacylation and deepoxidation. Essentially complete conversions to the deepoxy metabolites were observed for the non-acylated trichothecenes 4-deoxynivalenol, nivalenol, and verrucarol. However, deacetylation was the predominant pathway for the monoacetyl trichothecenes 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol (15ADON), and fusarenon X. Small amounts of the deepoxy metabolites were observed from 15ADON and large amounts from 15-monoacetoxyscirpenol where steric hindrance protected the C-15 acetyl groups from enzymatic attack. Diacetylated trichothecenes diacetoxyscirpenol and neosolaniol exhibited only deacetylation. The larger isovaleryl functionality was resistant to removal and deepoxidation was the prevalent reaction in HT-2 toxin and T-2 triol, whereas T2 toxin showed only deacetylation.

Animals↗

PubMed2006

Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone: an oestrogenic mycotoxin.

Zearalenone (ZEA) is a mycotoxin produced mainly by fungi belonging to the genus Fusarium in foods and feeds. It is frequently implicated in reproductive disorders of farm animals and occasionally in hyperoestrogenic syndromes in humans. There is evidence that ZEA and its metabolites possess oestrogenic activity in pigs, cattle and sheep. However, ZEA is of a relatively low acute toxicity after oral or interperitoneal administration in mice, rat and pig. The biotransformation for ZEA in animals involves the formation of two metabolites alpha-zearalenol (alpha-ZEA) and beta-zearalenol (beta-ZEA) which are subsequently conjugated with glucuronic acid. Moreover, ZEA has also been shown to be hepatotoxic, haematotoxic, immunotoxic and genotoxic. The exact mechanism of ZEA toxicity is not completely established. This paper gives an overview about the acute, subacute and chronic toxicity, reproductive and developmental toxicity, carcinogenicity, genotoxicity and immunotoxicity of ZEA and its metabolites. ZEA is commonly found on several foods and feeds in the temperate regions of Europe, Africa, Asia, America and Oceania. Recent data about the worldwide contamination of foods and feeds by ZEA are considered in this review. Due to economic losses engendered by ZEA and its impact on human and animal health, several strategies for detoxifying contaminated foods and feeds have been described in the literature including physical, chemical and biological process. Dietary intakes of ZEA were reported from few countries from the world. The mean dietary intakes for ZEA have been estimated at 20 ng/kgb.w./day for Canada, Denmark and Norway and at 30 ng/kgb.w./day for the USA. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) established a provisional maximum tolerable daily intake (PMTDI) for ZEA of 0.5 microg/kg of body weight.

Animal Feed↗

PubMed2004

Analysis of population structure of Aspergillus flavus from peanut based on vegetative compatibility, geographic origin, mycotoxin and sclerotia production.

Isolates of Aspergillus flavus obtained from a new growing peanut region in Argentina (Formosa province) were examined for aflatoxin types B and G and cyclopiazonic acid (CPA) production. Sclerotia diameters and the number of sclerotia produced per square centimetre were also determined for each isolate. They were tested by vegetative compatibility group analysis to investigate their genetic relatedness and correlate the results with vegetative compatibility groups previously described from the major peanut-growing area (Córdoba province) in our country. Two isolates were considered atypical because they simultaneously produce aflatoxins B and G and CPA. A. flavus population from Formosa province was very diverse genetically. Vegetative compatibility groups (VCGs) formed by typical isolations of A. flavus were different among agroecological sites. Formosa isolates could not be grouped to any of the Córdoba VCGs, while that one of the VCGs that contain atypical isolates included strains from the two geographical regions. Each VCG included isolates of the same mycotoxin and sclerotia production pattern. The two regions analysed have different climatic conditions, soil type, crop sequence history and also are in different latitude. These parameters may reflect different geographic adaptation between isolates from both sites.

Adaptation, Physiological↗

PubMed2006

Attenuation of mycotoxin-induced IgA nephropathy by eicosapentaenoic acid in the mouse: dose response and relation to IL-6 expression.

Clinical trials have revealed that progression of immunoglobulin A nephropathy (IgAN), the most common form of human glomerulonephritis, is inhibited by dietary (n-3) polyunsaturated fatty acid (PUFA) supplementation. The early stages of IgAN can be mimicked by feeding mice the mycotoxin deoxynivalenol (DON). Here, the effects of consuming the (n-3) PUFA eicosapentaenoic acid (EPA) on DON-induced IgAN were assessed relative to dose dependency and to expression of interleukin (IL-6). In the dose-response study, weight gain and feed intake did not differ among mice consuming 20 ppm DON supplemented with 0%, 0.1%, 0.5% and 3% EPA for 16 weeks. Mice fed the two highest EPA concentrations exhibited markedly increased splenic EPA, docosapentaenoic acid and docosahexaenoic acid, whereas arachidonic acid was decreased in all three EPA fed groups. Deoxynivalenol consumption significantly increased serum IgA and IgA immune complexes as well as kidney mesangial IgA deposition. All three IgAN markers were attenuated in mice fed 3% EPA diet but not in those fed 0.1% or 0.5% EPA. Elevated IgA production was observed in spleen and Peyer's patch (PP) cell cultures derived from mice fed DON in control diets, but this was reduced in cultures from mice fed 0.1%, 0.5% and 3% EPA. Acute DON exposure increased serum levels of IL-6, a cytokine that drives differentiation of IgA-committed B cells to IgA secretion. Relatedly, expression of IL-6 mRNA and IL-6 heteronuclear RNA, a marker of IL-6 transcription, was increased in spleen and PP. All three indicators of IL-6 expression were suppressed in mice consuming 3% EPA. Suppressed IL-6 corresponded to decreased binding activity of two factors that regulate transcription of this cytokine, cyclic AMP response element-binding protein and activator protein-1. The results indicate that a threshold existed for EPA relative to suppression of experimental IgAN and that the threshold dose was effective at inhibiting IL-6 transcription.

Animals↗

PubMed2005

Activation of ERK mitogen-activated protein kinase in human cells by the mycotoxin patulin.

Patulin (PAT), a mycotoxin produced by certain species of Penicillium and Aspergillus, is often detectable in moldy fruits and their derivative products. PAT led to a concentration-dependent and time-dependent increase in phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in human embryonic kidney (HEK293) cells, human peripheral blood mononuclear cells (PBMCs), and Madin-Darby canine kidney (MDCK) cells. Exposure of HEK293 cells to concentrations above 5 microM PAT for 30 min induced ERK1/2 phosphorylation; activation of ERK1/2 was also observed after 24 h incubation with 0.05 microM of PAT. Treatment of human PBMCs for 30 min with 30 microM PAT dramatically increased the phosphorylated ERK1/2 levels. Both MEK1/2 inhibitors, U0126 and PD98059, suppressed ERK1/2 activation in either HEK293 or MDCK cells. In HEK293 cells, U0126-mediated inhibition of PAT-induced ERK1/2 phosphorylation resulted in a significant decrease in levels of DNA damage, expressed as tail moment values, in the single cell gel electrophoresis assay. Conversely, U0126 did not affect cell viability, lactate dehydrogenase release, and the DNA synthesis rate in PAT-treated cultures. Exposure of HEK293 cells for 90 min to 15 microM PAT elevated the levels of early growth response gene-1 (egr-1) mRNA, but not of c-fos, fosB, and junB mRNAs. These results indicate that in human cells, PAT causes a rapid and persistent activation of ERK1/2 and this signaling pathway plays an important role in mediating PAT-induced DNA damage and egr-1 gene expression.

Animals↗