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PubMed1989

A dose-response analysis of methoxychlor-induced alterations of reproductive development and function in the rat.

In the present study rats were dosed from weaning, through puberty and gestation, to Day 15 of lactation with methoxychlor at 25, 50, 100, or 200 mg/kg/day. Morphological landmarks of puberty were measured, including the ages at vaginal opening, first estrus, and first estrous cycle in females and at preputial separation in males. In the female, estrous cyclicity, fertility, litter size, number of implantation sites, organ weights, and ovarian and uterine histology were also measured. The viability of the offspring (F1) and their fertility were evaluated using a continuous breeding protocol. Males were necropsied after breeding, the reproductive organs were weighed, and the cauda epididymal sperm counts were determined. One testis was used for histopathology, while the other was used to quantify interstitial fluid (IF) content, IF testosterone concentration, and testicular sperm production. Testosterone and androgen-binding protein were measured in the caput epididymis, and sperm motility and morphology were evaluated from a caudal sample. The serum and pituitary were saved for hormonal determinations. Methoxychlor accelerated the age at vaginal opening and first estrus, and the vaginal smears were cornified. Growth was retarded at 100 and 200 mg/kg/day and fertility was reduced when the females were bred with untreated or similarly treated males. In the highest-dose group, the mated females went from constant estrus into pseudopregnancy following mating, but they had no implants. In males, methoxychlor treatment markedly reduced growth, seminal vesicle weight, cauda epididymal weight, caudal sperm content, and pituitary weight. Puberty was delayed in the two highest-dosage groups. Testicular sperm measures were much less affected than caudal measures. Testis weight and histology were slightly affected, and testicular sperm production, sperm morphology, and motility were unaffected. Endocrine function of the testes and pituitary was altered by methoxychlor administration. Leydig cell testosterone production, in response to human chorionic gonadotropin challenge, was reduced and pituitary levels of prolactin, thyroid-stimulating hormone (TSH), and follicle-stimulating hormone (FSH) were altered. In contrast, serum levels of prolactin, FSH, and luteinizing hormone were unaffected. Serum TSH was reduced by 50% of control at 100 and 200 mg/kg/day, while pituitary levels were increased. Gonadotropin-releasing hormone concentration in the mediobasal hypothalamus was also elevated. In spite of the many reproductive alterations, the fertility of treated males was not reduced when they were mated with untreated females.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Protein secretions in mouse uterus after methoxychlor or estradiol exposure.

Four-month-old, ovariectomized mice were treated with 14 daily ip injections of either 10.0 micrograms of 17 beta-estradiol or 1.0 mg technical grade methoxychlor. Uterine luminal proteins were radiolabeled with 35S-methionine and run on 2-dimensional electrophoresis gels. The influence of methoxychlor or estradiol was compared to untreated controls by examining reproductive tract weights, uterine histology, and the patterns of uterine protein secretions. The data indicate that the stimulation of the uterus in ovariectomized, adult mice by methoxychlor is indistinguishable from that caused by estradiol. Both substances alter reproductive tract weights, promote cellular hypertrophy, stimulate uterine development, and induce the secretion of comparable levels of incorporation of methionine into a large number of proteins. The data further indicate that the alterations in gene expression promoted by estradiol in terms of secreted proteins appear to be qualitatively similar to those caused by the pesticide methoxychlor.

Animals↗
PubMed2005

Long term dietary methoxychlor exposure in rats increases sodium solution consumption but has few effects on other sexually dimorphic behaviors.

Methoxychlor is an insecticide with estrogen-like activity, thus exposure during development might cause sexually dimorphic behavioral alterations. To evaluate this, pregnant rats consumed diets containing 0, 10, 100 or 1000 ppm methoxychlor from gestational day 7, and offspring continued on these diets until postnatal day (PND) 77. Assessments of sexually dimorphic behaviors in offspring indicated that intake of a 3.0% sodium chloride solution was significantly increased (41%) in males and females of the 1000 ppm group. No treatment group differed from controls in open field nor running wheel activity, play behavior, nor 0.3% saccharin solution intake. Offspring of the 1000 ppm group showed significantly decreased body weight, reaching 17% less than controls at PND 77, but not clearly related to their salt solution intake. During pregnancy, 1000 ppm dams consumed 23% less food and weighed 10% less than controls, but this did not affect litter outcomes. These results indicate that in rodents, developmental and chronic exposure to dietary methoxychlor alters the sexually dimorphic behavior of salt-solution intake in young adults of both sexes. Similar behavioral alterations with other xenoestrogens, and the potential for interactions among xenoestrogens, suggest that this report may minimize the true effects of dietary methoxychlor exposure.

Animals↗
PubMed1973

Biomagnification of p, p'-DDT and methoxychlor by bacteria.

Aerobacter aerogenes and Bacillus subtilis accumulated p, p'-DDT and methoxychlor directly from water. Uptake of both (14)C-labeled organochlorine insecticides was rapid; 80 to 90% of the 24-h residues were reached within 30 min. Total cellular residues varied linearly with concentrations of DDT and methoxychlor in water ranging from 0.5 to 5.0 mug/liter. The residue magnification factors from water were between 1,400- to 4,300-fold, but were independent of insecticide concentrations in water. When the insecticide-exposed microbial cells were washed with pesticide-free water, DDT residues were 45% in A. aerogenes and 30% in B. subtilis, whereas the methoxychlor level decreased nearly 75% in both organisms. Subsequent washing did not further reduce the insecticide residue. Autoclave-killed bacteria also rapidly adsorbed DDT and methoxychlor from water and, in some instances, residues were higher than in the living cells. Molecular polarity and lipid solubility appear to influence the retention of the organochlorine insecticides by bacterial cells.

Autoradiography↗
PubMed2001

Effects of p-nonylphenol, methoxychlor, and endosulfan on vitellogenin induction and expression in sheepshead minnow (Cyprinodon variegatus).

Temporal and dose-response relationships of vitellogenin (VTG) mRNA induction and subsequent plasma VTG accumulation were established for sheepshead minnows (Cyprinodon variegatus) treated with p-nonylphenol (an alkylphenol) and the organochlorine pesticides methoxychlor and endosulfan. Thirty-two adult male fish per treatment were continuously exposed to measured concentrations of 0.64, 5.4, 11.8, 23.3, and 42.7 micrograms/L p-nonylphenol; 1.1, 2.5, 5.6, 12.1, and 18.4 micrograms/L methoxychlor; and in two separate tests, 15.9, 36.3, 68.8, 162, 277, 403, 590, and 788 ng/L endosulfan using an intermittent flow-through dosing apparatus. Separate triethylene glycol (50 microliters/L) and 17 beta-estradiol (65.1 ng/L) treatments served as the negative and positive controls, respectively. Four fish were randomly sampled from each test concentration on days 2, 5, 13, 21, 35, and 42 of exposure, and levels of hepatic VTG mRNA induction and serum VTG accumulation were determined for each individual. Overall, fish exposed to p-nonylphenol or methoxychlor demonstrated a rapid, dose-dependent synthesis of VTG mRNA up to day 5 of exposure, followed by a relatively constant dose-dependent expression through day 42. Both chemicals showed a dose-dependent increase in plasma VTG over the entire time course of exposure, with significantly elevated VTG levels by the fifth day of exposure to p-nonylphenol at concentrations of 5.4 micrograms/L or greater and to methoxychlor at concentrations of 2.5 micrograms/L or greater. Exposure to 0.64 microgram/L p-nonylphenol resulted in highly variable plasma VTG levels of less than 6 mg/ml. Exposures with endosulfan failed to induce measurable levels of either hepatic VTG mRNA or serum VTG at the chemical concentrations tested. Our results demonstrate that the sheepshead minnow bioassay is a suitable estuarine/marine teleost model for in vivo screening of potentially estrogenic substances.

Animals↗
PubMed2000

Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies.

We previously demonstrated differential interactions of the methoxychlor metabolite 2,2-bis(p-hydroxyphenyl)-1,1, 1-trichloroethane (HPTE) with estrogen receptor alpha (ERalpha), ERbeta, and the androgen receptor (AR). In this study, we characterize the ERalpha, ERbeta, and AR activity of structurally related methoxychlor metabolites. Human hepatoma cells (HepG2) were transiently transfected with human ERalpha, ERbeta, and AR plus an appropriate steroid-responsive luciferase reporter vector. After transfection, cells were treated with various concentrations of HPTE or structurally related compounds in the presence (for detecting antagonism) and absence (for detecting agonism) of 17beta-estradiol and dihydrotestosterone. The monohydroxy analog of methoxychlor, as well as monohydroxy and dihydroxy analogs of 2, 2-bis(p-hydroxyphenyl)-1,1-dichloroethylene, had ERalpha agonist activity and ERbeta and AR antagonist activity similar to HPTE. The trihydroxy metabolite of methoxychlor displayed only weak ERalpha agonist activity and did not alter ERbeta or AR activities. Replacement of the trichloroethane or dichloroethylene group with a methyl group resulted in a compound with ERalpha and ERbeta agonist activity that retained antiandrogenic activities. This study identifies some of the structural requirements for ERalpha and ERbeta activity and demonstrates the complexity involved in determining the mechanism of action of endocrine-active chemicals that simultaneously act as agonists or antagonists through one or more hormone receptors.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

Characteristics of monooxygenase-mediated covalent binding of methoxychlor in human and rat liver microsomes.

The characteristics of the activation of methoxychlor by the hepatic microsomal monooxygenases and its covalent binding to microsomal proteins in human and untreated rat were compared. The Vmax of covalent binding is similar in both species, being 21 and 11 pmol/min/mg protein in human and rat, respectively. However, their Kmapp values show marked differences: 146 versus 5 microM for human and rat, respectively. These differences in Km values seem to reflect the affinities of the respective P-450s for methoxychlor in catalyzing the formation of the reactive intermediate (M*) and not the availability of acceptor binding sites. The observations that alternate substrates and inhibitors of P-450 monooxygenases inhibit covalent binding of methoxychlor to human liver microsomes, demonstrate that covalent binding is catalyzed by typical monooxygenases. Antioxidants/free radical scavengers, and sulfhydryl-containing compounds inhibit covalent binding in human liver microsomes, suggesting that the reactive intermediate is a free radical. A similar finding in phenobarbital (Pb)-treated rats (Bulger, Temple and Kupfer, Toxicol. Appl. Pharmacol. 68:367, 1983) indicates that the mechanism of covalent binding in the two species is similar. Of interest is the observation with human liver samples that, despite differences in age, sex, and, probably, in diet among individuals, their rates of covalent binding of methoxychlor were similar. By contrast, there is a much higher covalent binding in the mature male rat than in the mature female or immature male or female rat, suggesting that developmentally controlled male-specific P-450s contribute to covalent binding in the adult male.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1977

Rapid preparation of micro sample and gas-liquid chromatographic determination of methoxychlor residues in animal tissues and water.

Methods are described for analyses of methoxychlor (2,2-bis(p-methoxyphenyl)-1,1,1-trichloroethane) in tissues of fish and invertebrate animals and in water samples. These micro methods offer economy in solvents and materials, and reduce health and fire hazards. Furthermore, the methods sufficiently reduce sample weights to allow analyses of small animals (mayflies) or animal organs. Samples are extracted in a ball-mill with n-hexane, and lipids are removed from fatty samples by freezeout. Small Florisil columns give final lipid cleanup and partial separation of methoxychlor from interfering materials. Methoxychlor is determined on a short gas-liquid chromatographic column (retention time 2.2 min). Animal tissue samples as small as 0.1 g and water samples of 5 ml can be analyzed at sensitivities of 10 and 1 ppb, respectively. Methoxychlor recoveries were 84-101% (fish and crab tissue), 92-100% (cod liver oil), and 98-107% (water) over a concentration range of 0.-10 ppm. Results obtained for fish tissue by using micro procedures agreed to within 20% of results reported by an independent laboratory using an established method.

Animals↗
PubMed1989

The impact of methoxychlor treatment of the saskatchewan river system on artificial substrate populations of aquatic insects.

The impact of methoxychlor exposure on aquatic insects inhabiting artificial substrates was monitored at three downstream sites relative to an upstream untreated site of the North Saskatchewan River. Treatment impact was studied for selected species of Simuliidae (Diptera), Perlodidae (Plecoptera), Hydropsychidae (Trichoptera), Baetidae and Heptageniidae (Ephemeroptera). At sites subjected to methoxychlor exposure which were 21, 38, and 107 km from injection, population changes varied depending on species and distance from the injection point. Although populations of some species were not significantly affected by treatment at any downstream site (P > 0.05), others were significantly reduced at one or more of the sites (P < 0.05- P < 0.01). Nymphs of Stenonema terminatum (Walsh) and Baetis tricaudatus Dodds (Ephemeroptera) apparently recolonized after dislodgement due to methoxychlor exposure. Species are categorized on the basis of their responses to methoxychlor treatment. Factors which probably caused different treatment impacts among species are discussed.

Journal Article↗
PubMed1978

Bioassay of methoxychlor for possible carcinogenicity.

A bioassay for possible carcinogenicity of technical-grade methoxychlor was conducted using Osborne-Mendel rats and B6C3F1 mice. Methoxychlor was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. For each species, 20 animals of each sex were placed on test as controls. The time-weighted average high and low dietary concentrations of methoxychlor were, respectively, 845 and 448 ppm for male rats, 1,385 and 750 ppm for female rats, 3,491 and 1,746 ppm for male mice, and 1,994 and 997 ppm for female mice. After a treatment period of 78 weeks, the rat groups were observed for an additional 34 weeks and the mouse groups for an additional 15 weeks. A dose-related mean group body weight depression was observed in both rats and mice, but no effect on survival was detected. Under the conditions of this study, methoxychlor was not found to be carcinogenic in Osborne-Mendel rats or B6C3F1 mice of either sex.

Journal Article↗
PubMedDate not supplied

Effect of transient embryonic in vivo exposure to the endocrine disruptor methoxychlor on embryonic and postnatal testis development.

The current study was designed to examine the effects of a transient embryonic exposure to the pesticide methoxychlor, an endocrine disruptor, on in vivo rat testis development and function. Gestating female rats were transiently administered methoxychlor (MXC) from embryonic day 7 (E7; EO = plug date) through E15. Embryonic testes were collected at E16 and postnatal (PO = day of birth) testes at P4, P10, P17-20, and P60. Seminiferous cords formed in testes from MXC exposed males. However, at E16, there was a decrease in the area of cords and an increase in interstitial area in MXC exposed testes when compared with controls. At all postnatal ages collected, there did not appear to be differences in seminiferous cord/tubule area, interstitial area, or number of seminiferous cords/tubules between untreated controls and males exposed to MXC. Exposure to the endocrine disruptor also had no effect on the postnatal organ weights of a variety of different organs, nor were testosterone levels altered. Interestingly, there were reductions in the number of germ cells in testes from MXC-exposed males at P17-P20 when compared with untreated controls. Furthermore, there was a twofold increase in apoptotic cells in tubules from pubertal P17-P20-MXC exposed males when compared with untreated controls. Testes were collected from adult P60 males to determine if early embryonic and postnatal alterations in germ cell numbers or testis cellular composition had compromised spermatogenesis. In adult P60 MXC exposed testes there were no gross morphological changes in testis structure or cellular composition over that of controls. However, there was an increase in apoptotic cell number in elongating spermatids in MXC exposed testes. Four P60 males that were exposed to MXC during gestation and 4 control males were bred with unexposed females to determine their ability to produce offspring. All MXC exposed males were capable of impregnating females and had normal litter size and pup weights. Combined observations demonstrated that exposure to MXC during gestation at a critical stage of testis development (ie, sex determination) affects embryonic testis cellular composition, germ cell numbers, and germ cell survival. While alterations in these parameters does not affect the ability of males to produce offspring, there appears to be a reduced spermatogenic capacity associated with MXC treatment. Therefore, transient embryonic exposure to an endocrine disruptor (methoxychlor) during gestation can influence the germline and fertility in adult males.

Animals↗
PubMed1987

Intramolecular deuterium isotope effect and enantiotopic differentiation in oxidative demethylation of chiral [monomethyl-d3]methoxychlor in rat liver microsomes.

Intramolecular deuterium kinetic isotope effects on the O-demethylation of methoxychlor [2,2-bis-(4-methoxyphenyl)-1,1,1-trichloroethane] were measured in liver microsomes taken from rats treated with phenobarbital or beta-naphthoflavone and from untreated rats. The substrates were (R)-, (S)- and racemic [monomethyl-d3]methoxychlor, and the ratio of [d3]- to [d0]-mono-O-demethylated metabolites was measured by GC-MS selected-ion monitoring. The magnitude of the observed ratio of [d3]- to [d0]-metabolites in each microsomal preparation was largest on the reaction of the (S)-substrate, followed by racemic substrate, and then (R). Each value is a composite of the intramolecular kinetic isotope effect and enantiotopic differentiation during the reaction. Each intramolecular isotope effect value estimated from these values was smaller than the reported intrinsic value. A relatively slow intramolecular interchange of two methoxyl groups in the methoxychlor molecule in the enzyme-substrate complex was indicated during the reaction. There also was evidence of high enantiotopic differentiation.

Animals↗
PubMed1997

Catalytic characteristics of CYP3A4: requirement for a phenolic function in ortho hydroxylation of estradiol and mono-O-demethylated methoxychlor.

CYP3A4 is the major human cytochrome P-450 in a superfamily of heme-thiolate proteins that catalyze the oxidation of numerous lipophilic compounds. In this investigation, we report that CYP3A4 requires a phenolic function for ortho hydroxylation of estradiol and mono-O-demethylated methoxychlor and that CYP3A4 aromatic hydroxylation in general may be dependent on the presence of a free phenolic group. Indeed, when methoxyls were present instead of phenolic hydroxyls, CYP3A4 essentially failed to catalyze ortho hydroxylation. By contrast, of eight additional cDNA-expressed P-450s (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, and 2E1) examined, only CYP1A2 and CYP2B6 could catalyze ortho hydroxylation of [o-3H]methoxychlor (7.2 and 14.6 pmol/90 min/pmol P-450, respectively), indicating that these isoforms do not require a phenolic hydroxyl for aromatic hydroxylation and that methoxyls do not sterically hinder catalysis by these CYPs. However, with [o-3H]mono-O-demethylated methoxychlor, containing a phenolic group, five isoforms (CYP1A2, 2B6, 2D6, 2E1, and 3A4) supported ortho hydroxylation. Of these, CYP3A4 exhibited by far the highest rate of hydroxylation at 87.8 pmol/90 min/pmol P-450. Further studies with [2-(3)H]estradiol 3-methyl ether and with [2-(3)H]estradiol revealed a similar and dramatic augmentation of CYP3A4-mediated C2 hydroxylase activity of approximately 75-fold by the presence of the phenolic group in the 3-position. The mechanism of augmentation by the phenolic hydroxyl does not appear to involve the acidic proton of estradiol, since CYP3A4-catalyzed estradiol 2-hydroxylation and testosterone 6-beta-hydroxylation were diminished to an equal extent when incubations were performed at increasing buffer pH values from 7 to 9. Both estradiol and its 3-methoxy derivative bound with similar affinity to cDNA-expressed, microsomal CYP3A4: spectral dissociation constants were 270 and 370 microM, respectively, and both compounds exhibited type I spectra. Thus, the disparities in aromatic hydroxylation rates between compounds containing phenolic hydroxyls and those with methoxyls cannot be explained by differences in their binding affinities. To explain the mode via which the phenolic hydroxyl facilitates ortho hydroxylation, a mechanism in which the phenolic moiety attacks the iron-oxo double bond of CYP3A4, resulting in oxygen transfer to the ortho position, is proposed. It is anticipated that these findings will assist in forecasting the CYP-mediated metabolic fate of phenolic compounds.

Cytochrome P-450 CYP3A↗
PubMedDate not supplied

Metabolism of methoxychlor by hepatic P-450 monooxygenases in rat and human. 1. Characterization of a novel catechol metabolite.

Previous investigations demonstrated that the incubation of the chlorinated hydrocarbon pesticide methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl)ethane] with rat liver microsomes generates phenolic estrogenic metabolites. The current study shows that the incubation of liver microsomes from untreated and phenobarbital-treated rats and human donors, in the presence of NADPH, yields three phenolic metabolites. Identification of the metabolites was achieved by TLC, HPLC, GC/MS, and LC/MS and by hydrodynamic voltammetric analysis. These metabolites were identified as the mon- and didemethylated phenolic derivatives (mono-OH-M and bis-OH-M, respectively) and as a novel trihydroxy derivative (tris-OH-M). The tris-OH-M was demonstrated to be a catechol [1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(3,4-dihydroxyphenyl)ethane]. Furthermore, the tris-OH-M becomes radiolabeled by [methyl-3H3]-S- adenosylmethionine (SAM) in a reaction catalyzed by catechol O-methyltransferase (COMT), indicating that tris-OH-M behaves like a catechol. Incubation of the monohydroxy metabolite with liver microsomes from phenobarbital-treated rats (PB microsomes) yields the dihydroxy and the trihydroxy metabolites. Furthermore, the time course of methoxychlor metabolism by PB microsomes demonstrated a rapid appearance and disappearance of the monohydroxy metabolite with the subsequent formation of the dihydroxy and trihydroxy metabolites. On the basis of these findings, it is proposed that the metabolic route of methoxychlor by mono-oxygenases involves sequential demethylations to the dihydroxy derivative and a subsequent ring hydroxylation.

Animals↗
PubMed2004

CYP2C subfamily, primarily CYP2C9, catalyses the enantioselective demethylation of the endocrine disruptor pesticide methoxychlor in human liver microsomes: use of inhibitory monoclonal antibodies in P450 identification.

1. The endocrine disruptor pesticide methoxychlor undergoes O-demethylation by mammalian liver microsomes forming chiral mono-phenolic (1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane, i.e. mono-OH-M) and achiral bis-phenolic oestrogenic metabolites. Human liver microsomes (HLM) generated primarily the S-mono-OH-M. 2. Inhibitory monoclonal antibodies (MAb) identified those P450s catalysing the enantioselective O-demethylation of methoxychlor. In HLM, O-demethylation was inhibited by MAb anti-2C9 (30-40%), diminishing the per cent of S-mono-OH-M from about 80 to 55-60%. MAb anti-CYP1A2, 2A6, 2B6, 2C8, 2C19, 2D6 and 3A4 did not affect the demethylation rate in HLM. Nevertheless, MAb anti-CYP1A2 decreased the formation of R-mono-OH-M from 21-23 to 10-17%, indicating that CYP1A2 exhibits a role in generating the R-enantiomer. 3. Among cDNA-expressed human P450s (supersomes), CYP2C19 was the most active in demethylation, but in HLM, CYP2C19 appeared inactive (no inhibition by MAb anti-CYP2C19). There was a substantial difference in the per cent inhibition of demethylation by MAb anti-CYP2C9 and anti-rat CYP2C (MAb inhibiting all human CYP2C forms) and in altering the enantioselectivity, suggesting that demethylation by combined CYP2C8, 2C18 and 2C19 was significant (20-30%). 4. Polymorphism of methoxychlor demethylation was examined with supersomes and HLM-expressing CYP2C9 allelic variants. CYP2C9*1 and 2C9*2 were highly active; however, CYP2C9*3 appeared inactive.

Alleles↗
PubMed1981

The persistence and disappearance by washoff and dryfall of methoxychlor from soybean foliage--a preliminary study.

The persistence and disappearance (washoff or dryfall) of methoxychlor [2,2-bis(p-methoxyphenyl)-1,1,1-trichloroethane] from mature soybean [Glycine max (L.) Merrill] foliage was investigated in a small field plot study under natural rainfall conditions in 1977 and 1978. Residue analyses were conducted using whole plant samples. Methoxychlor washoff rate was 8+/- 4% of the amount on plants (prior to rain) per centimeter of rainfall, regardless of time after application. Total seasonal washoff for 1978 accounted for 33.5% of the applied pesticide; however, 30.5% of the total loss was removed by washoff on the second day after application. Dryfall or dislodgeable residue accounted for less than 1% of the amount applied. The amount of dryfall was significantly greater in plots entered by workers than in those where entry was avoided. More than 19% of the applied methoxychlor was lost as a result of through-fall to the ground during application to the plots. Statistical analyses indicated that within-sample variation for mechanical chopping of plant samples was significantly smaller at the 5% level than for a hand chopping method. Results from this study will be useful in defining research objectives for the development of algorithms to describe the behavior of foliar-applied compounds. Such algorithms are necessary for estimating runoff losses of insecticides to water bodies.

Methoxychlor↗
PubMedDate not supplied

Attempted suicide by ingestion of methoxychlor.

A rare case involving an attempt to commit suicide by ingestion of a commercially available product containing methoxychlor as the active ingredient is presented. Clinical symptoms exhibited by the patient included no response to stimuli, pale skin, and profuse sweating. A serum sample collected at the time of admission to the hospital was found to contain 0.67 microg/mL of methoxychlor. The determination of methoxychlor was performed using gas chromatography-mass spectrometry.

Aged↗
PubMed2000

A metabolite of methoxychlor, 2,2-bis(p-hydroxyphenyl)-1,1, 1-trichloroethane, reduces testosterone biosynthesis in rat leydig cells through suppression of steady-state messenger ribonucleic acid levels of the cholesterol side-chain cleavage enzyme.

Postnatal development of Leydig cells involves transformation through three stages: progenitor, immature, and adult Leydig cells. The process of differentiation is accompanied by a progressive increase in the capacity of Leydig cells to produce testosterone (T). T promotes the male phenotype in the prepubertal period and maintains sexual function in adulthood; therefore, disruption of T biosynthesis in Leydig cells can adversely affect male fertility. The present study was designed to evaluate the ability of a xenoestrogen, methoxychlor (the methoxylated isomer of DDT [1,1, 1-trichloro-2,2-bis(p-chlorophenyl)ethane]), to alter Leydig cell steroidogenic function. Purified progenitor, immature, and adult Leydig cells were obtained from, respectively, 21-, 35-, and 90-day-old Sprague-Dawley rats treated with graded concentrations of the biologically active metabolite of methoxychlor, 2, 2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), and assessed for T production. HPTE caused a dose-dependent inhibition of basal and LH-stimulated T production by Leydig cells. Compared to the control value, reduced T production by progenitor and immature Leydig cells was apparent after 10 h of HPTE treatment in culture; the equivalent time for adult Leydig cells was 18 h. The reversibility of HPTE-induced inhibition was evaluated by incubating Leydig cells for 3, 6, 10, 14, or 18 h and measuring T production after allowing time for recovery. After treatment with HPTE for 3 h, T production by immature and adult Leydig cells for the 18-h posttreatment period was similar to the control value, but that of progenitor Leydig cells was significantly lower. The onset of HPTE action and the reversibility of its effect showed that Leydig cells are more sensitive to this compound during pubertal differentiation than in adulthood. T production was comparable when control and HPTE-treated immature Leydig cells were incubated with pregnenolone, progesterone, and androstenedione, but HPTE-treated Leydig cells produced significantly reduced amounts of T when incubations were conducted with 22R-hydroxycholesterol (P < 0.01). This finding suggested that HPTE-induced inhibition of T production is related to a decrease in the activity of cytochrome P450 cholesterol side-chain cleavage enzyme (P450(scc)) and cholesterol utilization. The reduced steady-state mRNA level for P450(scc) in HPTE-treated Leydig cells was demonstrated by reverse transcription-polymerase chain reaction and densitometry. In conclusion, this study showed that HPTE causes a direct inhibition of T biosynthesis by Leydig cells at all stages of development. This effect suggests that reduced T production could be a contributory factor in male infertility associated with methoxychlor and, possibly, other DDT-related compounds.

Animals↗