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PubMed2000

Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro.

Many pesticides are able to block or activate the steroid hormone receptors and/or to affect the levels of sex hormones, thereby potentially affecting the development or expression of the male and female reproductive system or both. This emphasizes the relevance of screening pesticides for a wide range of hormone-mimicking effects. Twenty-two pesticides were tested for their ability to affect CYP19 aromatase activity in human placental microsomes using the classical [(3)H](2)O method. Prochloraz, imazalil, propioconazole, fenarimol, triadimenol, triadimefon (all fungicides), and dicofol (an acaricide) gave rise to a statistically significant inhibition of aromatase activity. The IC(50)s of prochloraz, imazalil, propioconazole fenarimol, triadimenol, and triadimefon were calculated from dose-response curves to be 0.04, 0.34, 6.5, 10, 21 and 32 microM, respectively. The IC(50) of dicofol was greater than 50 microM. The positive control 4-hydroxyandrostendione (1 microM) caused an inhibition of aromatase activity by 74%. The compounds, which did not affect the aromatase activity, were bromopropylate, chlorfenvinphos, chlorobenzilate, chlorpyrifos, diuron, heptachlor, iprodion, linuron, pentachlorphenol, procymidon, propyzamide, quintozen, tetrachlorvinphos and tetradifon. With the purpose of comparing the results for fenarimol obtained with the microsomal system with data from an intact cell system, an aromatase assay based on JEG-3 cells was established. 4-Hydroxyandrostendione (1 microM) inhibited the aromatase activity in JEG-3 cells by 94%. The IC(50) for fenarimol in this system was 2 microM, slightly lower than that observed in the microsomal system. For the first time, fenarimol has been demonstrated to inhibit aromatase activity in human tissues and, furthermore, propioconazole, triadimefon, and triadimenol were identified as weak aromatase inhibitors. In conclusion, seven out of 22 tested pesticides turned out to be weak to moderate aromatase inhibitors in vitro, indicating the relevance of elucidating the endocrine effects in vivo of these- compounds.

Aromatase Inhibitors↗

PubMed1999

Mode of action of pesticides on aflatoxin biosynthesis and oxidase system activity.

The effects of nine pesticides on the biosynthesis of aflatoxin and oxidase activity in wild-type Aspergillus flavus and mutant strains of A. parasiticus avr-1 (w 49) and A. parasiticus ver-1 (wh 1) were investigated. In A. parasiticus, phosphonic acid derivative (lancer) reduced the formation of aflatoxin B2 but B1, G1 and G2 and anthraquinones (versicolorin A, versiconal hemiacetal acetat and averufin) accumulated. Phosphorothioic acid derivatives (pirimiphos-methyl and pyrazophos) reduced the formation of aflatoxin B2 and G2 but B1 and G1 and anthraquinones accumulated. Phosphorodithioic acid derivatives (dimethoate and malathion) blocked aflatoxin B2, reduced B1 and G2 but G1 and anthraquinones accumulated. Phosphoric acid derivative (profenfos) inhibited the formation of all aflatoxins, versicolorin A and versiconal hemiacetal acetate but averufin accumulated. The phenylurea derivatives (linuron and pencycuron) at concentrations of 500 and 1000 ppm inhibited all aflatoxin but anthraquinones accumulated. On the other hand, the dicarboximide derivative (iprodione) inhibited the whole pathway in the mutant strains of A. parasiticus. The oxidase system in wild-type A. flavus was active in the conversion of averufin and versicolorin A into aflatoxin B1. Most organophosphate and phenylurea derivatives may competitively increase or decrease the oxidase enzymes, however, profenfos and iprodione blocked the enzymes between averufin and versicolorin A.

Aflatoxins↗

PubMed1997

Baker's yeast biomass (Saccharomyces cerevisae) for selective on-line trace enrichment and liquid chromatography of polar pesticides in water.

Baker's yeast cells (Saccharomices cerevisae) were successfully immobilized onto silica gel and used in the on-line isolation and trace enrichment of desisopropylatrazine, desethylatrazine, hydroxyatrazine, simazine, cyanazine, atrazine, carbaryl, propanil, linuron, and fenamiphos. Since humic and fulvic acids were not coextracted, no cleanup was necessary. The pesticides were spiked at 0.1-1 microgram L-1 in tap water, groundwater, and seawater and were preconcentrated using on-line solid-phase extraction into a yeast immobilized on silica gel precolumn followed by liquid chromatography with diode array detection. All the variables that affect the enrichment step, such as amount of yeast immobilized, dimensions of the precolumn, sample pH, and preconcentration flow rate, were optimized. The degree of selectivity was evaluated by comparing the chromatograms obtained after on-line sample preconcentration on the yeast precolumn with those obtained by on-line solid-phase extraction using a precolumn filled with C18 material. The relative standard deviation for the whole procedure in the determination of the selected pesticides at the 0.3 microgram L-1 concentration level ranged from 1 to 9%, depending on the pesticide and the type of water. Detection limits within the range 0.01-0.5 microgram L-1 were obtained by percolating only 25 mL of water sample without any additional cleanup step.

Biomass↗

PubMed2004

Cloning and in vitro expression and characterization of the androgen receptor and isolation of estrogen receptor alpha from the fathead Minnow (Pimephales promelas).

In vitro screening assays designed to identify hormone mimics or antagonists typically use mammalian (rat, human) estrogen (ER) and androgen receptors (AR). Although we know that the amino acid sequences of steroid receptors in nonmammalian vertebrates are not identical to the mammalian receptors, a great deal of uncertainty exists as to whether these differences affect interactions of potential endocrine-disrupting chemicals (EDC) with the receptors. This leads to substantial uncertainty with respect to the utility of mammalian-based screening assays to predict possible effects of EDCs in nonmammalian wildlife. This paper describes preparation of a cDNA library from a small fish model commonly used in ecological risk assessments, the fathead minnow (Pimphales promelas). The cDNA library was subsequently used to isolate and sequence both AR and ERalpha. In addition, the fathead minnow (fh)AR was expressed and characterized with respect to function using saturation and competitive binding assays in COS monkey kidney cells. Saturation experiments along with subsequent Scatchard analysis determined that the Kd of the fhAR for the potent synthetic androgen R1881 was 1.8 nM, which is comparable to that for the human AR in the same assay system. In COS whole cell competitive binding assays, potent androgens such as dihydrotestosterone and 11-ketotestosterone were also shown to be high affinity ligands for the fhAR. We also report affinity of the receptor for a number of environmental contaminants including the AR agonists androstenedione and 17a- and 17beta-trenbolone;AR antagonists such as p,p'-DDE, linuron, and vinclozolin; and the ER agonist 17beta-estradiol. Future plans include comparison of binding affinities of the fhAR to those of the human AR, also expressed in COS cells, using a range of EDCs.

Androgen Antagonists↗

PubMed2000

Multiresidue HPLC methods for phenyl urea herbicides in water.

High-performance liquid chromatography (HPLC) methods for the determination of phenyl urea herbicides in water are described. The target compounds include chlortoluron, diuron, fluometuron, isoproturon, linuron, metobromuron, metoxuron, monuron, neburon, and siduron. Water was subjected to solid phase extraction (SPE) using either automated SPE with 47 mm C(18) Empore disks or on-line precolumn concentration. Herbicides were separated on a C(18) reversed phase column with an acetonitile-water gradient and were detected with either a diode array detector (DAD) or a postcolumn photolysis and derivatization (PPD) detector system. Photolysis converted the phenyl ureas to monoalkylamines that were derivatized to fluorescent isoindoles by reaction with o-phthalaldehyde and 2-mercaptoethanol. The DAD monitoring at 245 nm was linear over three decades with instrument detection limits of approximately 0.01 mg/L. SPE efficiency was between 48 and 70% in laboratory reagent water, but use of the internal standard quantitation method improved accuracy. High total dissolved solids and total organic carbon values in surface water improved recoveries relative to laboratory reagent water for all of the phenyl ureas. In Colorado River water spiked at 1 or 50 microg/L, mean recoveries ranged from 74 to 104%. Method detection limits (MDLs) ranged from 4 to 40 ng/L (parts per trillion) with the DAD instrument. PPD detection was highly specific but resulted in a slight loss in chromatographic efficiency and average MDLs approximately 5 times higher using a single set of detection conditions. The study indicates that methods based on SPE followed by HPLC with diode array or PPD detection have practical utility for trace analysis of phenyl ureas in drinking water or surface waters.

Chromatography, High Pressure Liquid↗

PubMed1997

Determination of genotoxicity of the metabolites of the pesticides Guthion, Sencor, Lorox, Reglone, Daconil and Admire by 32P-postlabeling.

Commercial formulations of the pesticides: Guthion (azinphos methyl), Sencor (metribuzin), Lorox (linuron), Reglone (diquat), Daconil (chlorothalonil) and Admire (imidacloprid) were studied for their genotoxicity by 32P-postlabeling. Metabolites of the pesticides were obtained enzymatically using arochlor induced rat liver S9 fraction, in an NADPH generating system. The resulting metabolites were reacted with calf thymus DNA and the DNA was analyzed for presence of adducts by either the nuclease P1 or butanol enrichment. Nuclease P1 enrichment resulted in adducts for all the pesticides. Compared to the level of adducts in control DNA, the levels in pesticide-treated DNA were higher for all the pesticides, except Daconil. The increase in adduct numbers for pesticide-treated DNAs ranged from 4.9-12.4 times the control-DNA indicating pesticide genotoxicity in this in vitro system. Enrichment using butanol extraction gave three adducts unique to Sencor-DNA. These adducts were different from those obtained with nuclease P1 enrichment of the same. B(alpha)P was the positive control for the in vitro metabolism, and two adduct enrichment procedures: nuclease P1 digestion and butanol extraction.

Adenosine Triphosphate↗

PubMed1997

Mixed immunosorbent for selective on-line trace enrichment and liquid chromatography of phenylurea herbicides in environmental waters.

An immunosorbent containing antiisoproturon and antichlortoluron antibodies immobilised on aldehyde-activated silica was employed for the on-line preconcentration and liquid chromatography-diode array detection of several phenylureas. The efficiency of the coupling of the immunosorbent to the liquid chromatographic system and the characteristics of the immunosorbent were evaluated. The on-line system allowed the selective trace enrichment of chlortoluron, isoproturon, metobromuron, linuron and chlorbromuron at the 0.05-0.5 microgram l-1 level in ground and river waters and provided detection limits in the range 0.01-0.03 microgram l-1 by percolating only 10 ml of water sample. The proposed method was validated by analysing freeze-dried tap water samples with a high content in pesticides of different chemical functionalities. The results obtained were compared with the mean value obtained in an interlaboratory exercise.

Chromatography, Liquid↗

PubMed1998

Isolation of isoproturon-degrading bacteria from treated soil via three different routes.

Three different isolation routes (flask enrichment/flask degradation assay, flask enrichment/microplate degradation assay, MPN assay/microplate degradation assay) were used to obtain pure cultures of bacteria which degraded isoproturon (3-(4-isopropylphenyl)-1,1-dimethylurea) as sole carbon and nitrogen source in a mineral salts medium from a field soil treated with isoproturon in the laboratory. All three isolation routes were successful, but the microplate assay of degradation was more successful than the flask assay. Characterization of 36 isolates indicated that they formed 16 distinct phenotypes (10 Gram-positive phenotypes, six Gram-negative phenotypes) which are likely to represent distinct species. Low concentrations of the degradation product 3-(4- isopropylphenyl)-1-methylurea (IPPMU) were occasionally found in the culture solutions. When provided as the sole source of carbon and nitrogen, the monomethyl degradation product was itself rapidly degraded by several of the isolates. Some isolates were also able to use the demethylated degradation product 3-(4-isopropylphenyl)-urea (IPPU) as sole source of carbon and nitrogen, although there was occasionally an extended lag-phase before rapid degradation commenced. One isolate was particularly active and degraded isoproturon, the monomethyl and demethylated degradation products of isoproturon, and demethylated the related phenylureas diuron and linuron.

Bacteria↗

PubMed2002

Mycorrhizal growth in pure cultures in the presence of pesticides.

The effects of pesticides on 64 ectomycorrhizal fungi of boreal forest trees were studied in vitro. The pesticides (fungicides: benomyl, chlorothalonil, copper oxychloride, maneb and propiconazole; herbicides: chlorthiamid, glyphosate, hexazinone, linuron and terbuthylazine; insecticide: cypermethrin) were selected as those commonly used in Nordic forest nurseries and afforestation sites. In general, the fungicides proved to be more toxic to ectomycorrhizal fungi than the herbicides and cypermethrin. The fungicides, chlorothalonil and propiconazole, had the clearest inhibitory effect on growth of mycorrhizal fungi. Conversely, maneb, glyphosate and terbuthylazine stimulated the growth of some mycorrhizal fungi. Leccinum versipelle and L. scabrum, Paxillus involutus and Cenococcum geophilum were the most sensitive ectomycorrhizal fungi to the various pesticides.

Colony Count, Microbial↗

PubMed1999

Screening of selected pesticides for oestrogen receptor activation in vitro.

Twenty pesticides were tested for their ability to activate the oestrogen receptor in vitro using an MCF7 cell proliferation assay and a Yeast Oestrogen Screen. The fungicides fenarimol, triadimefon, and triadimenol were identified as weak oestrogen receptor agonists, which at 10 microM induces a 2.0, 2.4, and 1.9-fold increase in proliferation of human MCF7 breast cancer cells (E3 clone). The relative proliferation efficiency (RPE) was 43-69%, indicating partial agonism at the oestrogen receptor. Several pesticides did not have any effect on the proliferation response after 6 days of exposure, including: chlorpyrifos, diuron, iprodion, linuron, pentachlorphenol, prochloraz, propioconazol, propyzamine, quintozen, tetrachorvinphos and tetradifon. Some pesticides resulted in a negligible proliferation response, which was not statistically significant under the present experimental conditions. These were: bromopropylate, chlorfenvinphos, chlorobenzilate, dicofol, heptachlor, and imazalil. Fenarimol and dicofol also gave rise to a positive oestrogenic response in yeast cells transfected with the oestrogen receptor alpha, whereas the remaining compounds resulted in a negative response due either to biological inactivity or cytotoxocity to the yeast cells. The EC50 for fenarimol was estimated to be 13 microM in the yeast cells, compared with an EC50 of 3 microM in the MCF7 cells, indicating higher sensitivity of the latter assay. No in vivo data for fenarimol, triadimefon or triadimenol have previously been published that support oestrogenic activity in the intact animal. Thus, from the present results we suggest that oestrogen receptor activation may not be an important mode of action for these compounds. The need to include at least two bioassays in a screening procedure and for combining in vitro and in vivo data is emphasized.

Cell Line↗

PubMed2001

Organic pollutants in surface waters from Portugal using chemometric interpretation.

Surface water samples from 45 sampling points across Portugal have been analyzed monthly by automated Solid Phase Extraction (SPE) and Gas Chromatography-Mass Spectrometry (GC/MS) in SIM and SCAN modes. Sampling was carried out during a period of six months (April-September, 1999), in order to determine the levels of contamination of 72 organic compounds mainly selected from the EC Council Directive list (CEC 76/464/EEC). Atrazine, simazine, deethylatrazine, alachlor, metolachlor, Irgarol, terbuthylazine, tributhylphosphate, 2,4,6-trichlorophenol, 2-chlorophenol, 3-chlorophenol, pentachlorophenol, dimethoate, lindane, linuron, propanil, o,p'-DDD, o,p'-DDT, o,p'-DDE and malathion were the main detected compounds. Although Irgarol, terbuthylazine, deethylatrazine and deisopropylatrazine are not listed in the EC Directive, these herbicides and transformation products are currently in use and they were also included in the monitoring program and detected at some sites. Fifty-nine percent of the samples were below 0.1 microg l(-1), the detection limit required the EEC Drinking Water Directive (DWD). Some compounds were detected at values higher than the DWD, e.g. atrazine (2.7 microg l(-1)) and alachlor (5.43 microg l(-1)) in April. Simazine was also present with a high value (2.3 microg l(-1)) in September. Tributhylphosphate (5.40 microg l(-1)) and 2,4,6-trichlorophenol (2.31 microg l(-1)) were also found at high concentrations near industrial sites. Chemometric interpretation of the more representative contaminants was performed by means of Principal Component Analysis, allowing the resolution of the more relevant contamination sources and the description of their temporal and spatial (geographical) distributions.

Environmental Monitoring↗

PubMed1990

Biomonitoring of arylamines: hemoglobin adducts of urea and carbamate pesticides.

Hemoglobin adducts of aromatic amines released from pesticides were investigated. Female Wistar rats were dosed orally with pesticides up to 1 mmol/kg body weight. Blood was obtained after 24 h, hemoglobin isolated and hydrolyzed in 1 NaOH. The amines were extracted and quantified by gas chromatography with nitrogen-specific or mass-selective detection. The following binding indices [HBI, hemoglobin binding index = binding (mmol/mol Hb) per dose (mmol/kg)] were obtained: pesticide (arylamine): linuron, diuron (3,4-dichloroaniline) 0.8 and 4.5 respectively; monuron, monolinuron (4-chloroaniline) 39 and 55 respectively; chlorpropham (3-chloroaniline) 2.9; chlordimeform (4-chloro-o-toluidine) 2.4; propham (aniline) 2.4. With vinclozoline and iprodione (3,5-dichloroaniline) and quintozene (pentachloroaniline) no adducts could be found. The results demonstrate the possible use of arylamine-hemoglobin adducts for measuring the bioavailability of potentially hazardous components of pesticides and the extent to which they are formed and metabolically activated.

Animals↗

PubMed1999

High-performance liquid chromatography column switching applied to the trace determination of herbicides in environmental and drinking water samples.

A selective and sensitive coupled-column high-performance liquid chromatographic method is developed for the simultaneous determination of 5 phenylurea herbicides (monuron, linuron, isoproturon, monolinuron, and diuron) in environmental and drinking water samples. Sample clean-up is performed automatically by means of a column switching technique. Using 2 octadecyl silica columns connected via two programmable 6-port valves and ultraviolet detection at 244 nm, the aforementioned compounds can be determined at the low concentration levels required for pesticide residue analysis in water samples. A mobile phase consisting of a mixture of methanol-water (55:45, v/v) is pumped at 1 mL/min. For the 5 phenylureas, high recoveries ranging from 94.9 to 101.6%, good reproducibility with relative standard deviations lower than 5%, and wide linear ranges up to 20 micrograms/L are observed with determination limits of 0.05 microgram/L. The method is successfully applied to the screening of different environmental water samples such as surface, ground, rain, and drinking water.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

Effects of environmental antiandrogens on reproductive development in experimental animals.

Chemicals that act as androgen receptor (AR) agonists and antagonists or inhibit fetal steroidogenesis can induce reproductive malformations in humans and laboratory animals. Several environmental chemicals disrupt development in rats and/or rabbits at fetal concentrations at, or near, exposure levels seen in some segments of the human population. In rats, fetal tissues concentrations of 10-20 p.p.m. of the DDT metabolite, p,p'-DDE, are correlated with reproductive abnormalities in male offspring. These concentrations are similar to those measured in first-trimester human fetal tissues in the late 1960s. The pesticides vinclozolin, procymidone, linuron and DDT are AR antagonists. They reduce male rat anogenital distance, and induce areolas at relatively low dosages. Hypospadias, agenesis of the sex accessory tissues and retained nipples are seen in the middle dosages, while undescended testes and epididymal agenesis are seen in the highest doses. Phthalate esters (PE) inhibit testosterone synthesis during fetal life, but do not appear to be AR antagonists. Prenatal administration of a single low dose of dioxin (50-1,000 ng TCDD/kg) alters the differentiation of androgen-dependent tissues at p.p.t. concentrations, but the mechanism of action likely involves interaction with a hormone-like nuclear transcription factor, the hormone-like receptor AhR, rather than AR. p,p'-DDT and p,p'-DDE, vinclozolin and di-n-butyl phthalate affect reproductive function in rabbits when administered during prenatal and/or neonatal life. Cryptorchidism and carcinoma in situ-like (CIS) testicular lesions were seen in male rabbits treated during development with p,p'-DDT or p,p'-DDE. Extrapolation of effects from rodents to humans would be enhanced if future studies incorporate determination of tissue concentrations of the active metabolites. Knowledge of the tissue concentrations of the active toxicants also would provide an important link to in-vitro studies, which provide more useful mechanistic information when they are executed at relevant concentrations.

Androgen Antagonists↗

PubMed2001

Androgen receptor antagonism by the organophosphate insecticide fenitrothion.

Organophosphate insecticides represent one of the most widely used classes of pesticides with high potential for human exposure in both rural and residential environments. We investigated the interaction of the organophosphothioate pesticide fenitrothion (O,O-dimethyl O-(4-nitro-m-tolyl) phosphorothioate) with the human androgen receptor (AR). Fenitrothion blocked dihydrotestosterone-dependent AR activity in a concentration-dependent and competitive manner in HepG2 human hepatoma liver cells transiently transfected with human AR and an AR-dependent luciferase reporter gene. Schild regression analysis yielded an equilibrium dissociation constant value of 2.18 x 10(-8) M. To determine the antiandrogenic potential of fenitrothion in vivo, 7-week-old castrated Sprague-Dawley rats were dosed once a day for 7 days with testosterone propionate (50 microg/day, sc) plus gavage doses of either corn oil vehicle or fenitrothion (15 or 30 mg/kg/day). An additional group of rats was given testosterone propionate and flutamide (50 mg/kg/day). Motor activity and acetylcholinesterase activity in whole blood and brain were also assessed. Both fenitrothion and the reference antiandrogen flutamide caused significant decreases in the ventral prostate, seminal vesicle, and levator ani plus bulbocavernosus muscles tissue weights. In contrast, blood acetylcholinesterase activity, a standard biomarker of organophosphate poisoning, was only inhibited at the higher dose of fenitrothion (30 mg/kg). Our results demonstrate that fenitrothion is a competitive AR antagonist, comparable in potency to the pharmaceutical antiandrogen flutamide and more potent, based on in vitro assays, than the known environmental antiandrogens linuron and p,p'-, 2,2-bis(p-hydroxyphenyl)-1,1-dichloroethylene ( p,p'-DDE).

Acetylcholinesterase↗

PubMed2002

A novel cell line, MDA-kb2, that stably expresses an androgen- and glucocorticoid-responsive reporter for the detection of hormone receptor agonists and antagonists.

The U.S. Environmental Protection Agency has proposed that in vitro assays for estrogen receptor (ER)- and androgen receptor (AR)-mediated actions be included in a Tier-I screening battery to detect hormonally active chemicals. Herein we describe the development of a novel stable cell line, MDA-kb2, for screening of androgen agonist and antagonists and to characterize its specificity and sensitivity to endocrine-disrupting chemicals. The breast cancer cell line, MDA-MB-453, was stably transformed with the MMTV.luciferase.neo reporter gene construct. Since both GR and AR are present in the MDA-MB-453 cells, and both receptors can act through the MMTV promoter, compounds that act through either AR or GR activate the MMTV luciferase reporter. As expected, AR agonists such as dihydrotestosterone (DHT), and GR agonists such as dexamethasone (DEX), corticosterone, and aldosterone induce luciferase expression at appropriate concentrations. DHT consistently produced 3-9-fold induction at concentrations from 0.1 to 10 nM. At 1 to 1000 nM, DEX induced luciferase activity 1.3-19.5-fold. To distinguish AR- from GR-mediated ligands, chemicals were assayed concurrently with the antiandrogen, hydroxyflutamide (OHF), which blocks AR- but not GR-mediated responses. In addition, known AR antagonists, including hydroxyflutamide, vinclozolin, vinclozolin metabolites M1 and M2, p,p'-DDE, and linuron inhibited DHT-induced luciferase gene expression at appropriate concentrations in this system. We have found that these cells are relatively easy to culture and maintain. Responsiveness was monitored over time and was stable for more than 80 passages. Some advantages of this assay are that it is relatively rapid (2 days), eliminates the need for transfection, can be conducted in a 96-well plate format, and produces consistent reproducible results. In summary, we have developed a cell line that can be used to screen chemicals, not just for AR- but for GR-mediated activities as well.

Androgen Antagonists↗

PubMed2002

Effects of in utero exposure to the organophosphate insecticide fenitrothion on androgen-dependent reproductive development in the Crl:CD(SD)BR rat.

Fenitrothion [0,0-dimethyl-O-(4-nitro-m-tolyl) phosphorothioate] is an organophosphate insecticide that has been shown to have antiandrogenic activity using in vitro and in vivo screening assays. Studies were performed to evaluate the ability of fenitrothion to disrupt androgen-dependent sexual differentiation in the male rat. Pregnant Crl:CD(SD)BR rats were administered fenitrothion by gavage at 0, 5, 10, 15, 20, or 25 mg/kg/day ( n = 6-11/group) from gestation day (GD) 12 to 21. Maternal toxicity was observed in the dams treated with 20 and 25 mg fenitrothion/kg/day based on muscle tremors and decreases in body weight gain from GD 12 to 21. Fetal death was increased in the 20 and 25 mg/kg/day exposure groups, as evidenced by a decrease in the proportion of pups born alive. Androgen-mediated development of the reproductive tract was altered in male offspring exposed in utero to maternally toxic levels of fenitrothion (25 mg/kg/day), as evidenced by reduction in anogenital distance on postnatal day (PND) 1 and retention of areolae on PND 13. However, these effects were only transient, and there were no indications of abnormal phenotypes or development of androgen-dependent tissues on PND 100. At the dose levels evaluated in this study, fenitrothion was only weakly antiandrogenic in vivo compared with other androgen receptor antagonists such as flutamide, linuron, and vinclozolin. Based on observed fetotoxicity at 20 mg/kg/day, the lowest observed adverse effect level (LOAEL) for developmental effects can be lowered from 25 to 20 mg/kg/day.

Abnormalities, Drug-Induced↗

PubMed2002

Engineering herbicide metabolism in tobacco and Arabidopsis with CYP76B1, a cytochrome P450 enzyme from Jerusalem artichoke.

The Jerusalem artichoke (Helianthus tuberosus) xenobiotic inducible cytochrome P450, CYP76B1, catalyzes rapid oxidative dealkylation of various phenylurea herbicides to yield nonphytotoxic metabolites. We have found that increased herbicide metabolism and tolerance can be achieved by ectopic constitutive expression of CYP76B1 in tobacco (Nicotiana tabacum) and Arabidopsis. Transformation with CYP76B1 conferred on tobacco and Arabidopsis a 20-fold increase in tolerance to linuron, a compound detoxified by a single dealkylation, and a 10-fold increase in tolerance to isoproturon or chlortoluron, which need successive catalytic steps for detoxification. Two constructs for expression of translational fusions of CYP76B1 with P450 reductase were prepared to test if they would yield even greater herbicide tolerance. Plants expressing these constructs had lower herbicide tolerance than CYP76B1 alone, which is apparently a consequence of reduced stability of the fusion proteins. In all cases, increased herbicide tolerance results from more extensive metabolism, as demonstrated with exogenously fed phenylurea. Beside increased herbicide tolerance, expression of CYP76B1 has no other visible phenotype in the transgenic plants. Our data indicate that CYP76B1 can function as a selectable marker for plant transformation, allowing efficient selection in vitro and in soil-grown plants. Plants expressing CYP76B1 may also be a potential tool for phytoremediation of contaminated sites.

7-Alkoxycoumarin O-Dealkylase↗