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PubMed2004

Glucuronidation of the oxidative cytochrome P450-mediated phenolic metabolites of the endocrine disruptor pesticide: methoxychlor by human hepatic UDP-glucuronosyl transferases.

Methoxychlor, a currently used pesticide, is a proestrogen exhibiting estrogenic activity in mammals in vivo. Methoxychlor undergoes oxidative metabolism by cytochromes P450, yielding 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane (mono-OH-M) and 1,1,1-trichloro-2,2-bis(4-hydroxyphenyl)ethane (bis-OH-M) as main metabolites. Since humans may be exposed to these estrogenic metabolites, which are potential substrates of UDP-glucuronosyltransferases (UGTs), their glucuronide conjugation was investigated with human liver preparations and individual UGTs. Incubation of both mono-OH-M and bis-OH-M with human liver microsomes formed monoglucuronides. The structures of the glucuronides were identified by liquid chromatography/tandem mass spectometry. Examination of cDNA-expressed recombinant human hepatic UGTs revealed that several catalyze glucuronidation of both compounds. Among the cDNA-expressed UGT1A enzymes, UGT1A9 seemed to be the main catalyst of formation of mono-OH-M-glucuronide, whereas UGT1A3 seemed to be the most active in bis-OH-M-glucuronide formation. Furthermore, the chiral selectivity of mono-OH-M glucuronidation was examined. The results of the incubation of single enantiomers generally agreed with the chiral analyses of mono-OH-M derived from the glucuronidase digestion of the glucuronides of the racemic mono-OH-M. There was a relatively slight but consistent enantioselective preference of individual UGT1A1, UGT1A3, UGT1A9, and UGT2B15 enzymes for glucuronidation of the S- over the R-mono-OH-M, whereas in human liver microsomes differences were observed among donors in generating the respective R/S-mono-OH-M ratio. Since it was previously shown that human liver microsomes demethylate methoxychlor mainly into S-mono-OH-M, the observation that UGT1A isoforms preferentially glucuronidate the S-mono-OH-M suggests a suitable mechanism for eliminating this major enantiomer. This enantiomeric preference, however, is not extended to all samples of human liver microsomes that we tested.

Blotting, Western↗
PubMedDate not supplied

The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats.

This study was designed to determine if long-term exposure to high doses of methoxychlor (M) would alter pituitary or testicular endocrine functions in either an estrogenic or antiandrogenic manner. Weanling male Long-Evans hooded rats were dosed daily with M (po) at 0, 200, 300, or 400 mg kg-1 day-1 for 10 months. Methoxychlor treatment delayed puberty by as much as 10 weeks and reduced fertility and copulatory plug formation in a dose-related manner at the initial mating. During mating, M-treated males exhibited shorter latencies to mount and ejaculate versus control males, but the number of intromissions prior to ejaculation was unaffected, indicating that M enhanced the arousal level in the males in an estrogen-dependent manner. Most treated males eventually mated but time-to-pregnancy was lengthened. Very low sperm counts were associated with infertility, while prolonged delays in puberty reduced fecundity. Methoxychlor treatment with 200 to 400 mg kg-1 day-1 failed to mimic the chronic effects of a sustained (8 months) low dose of estradiol-17 beta (3-mm silastic implants) on pituitary or testicular hormone levels. Estradiol administration increased pituitary weight 4-fold, serum levels of luteinizing hormone (LH) were reduced by almost 50%, and serum prolactin was increased 40-fold, while M did not affect any of these measures. These data demonstrate that M affects the CNS, epididymal sperm numbers, and the accessory sex glands and delays mating without significantly affecting the secretion of LH, prolactin, or testosterone. These data indicate that M did not alter pituitary endocrine function in either an estrogenic or antiandrogenic manner. To our knowledge, these data provide the first in vivo example of such a pronounced degree of target tissue selectivity to an environmental endocrine-disrupting chemical.

Animals↗
PubMed2004

Interactive effects of p,p'-dichlorodiphenyldichloroethylene and methoxychlor on hormone synthesis in largemouth bass ovarian cultures.

p,p'-Dichlorodiphenyldichloroethylene (DDE) and methoxychlor were tested alone and in combination to assess the similarity of their actions on hormone synthesis in gonadal tissue from largemouth bass (Micropterus salmoides floridanus), a species whose reproductive fitness has relevance to ecosystem health in Florida (USA). Gonads were harvested from adult female bass (age, two to three years) during the peak reproductive season (January-May), minced, and incubated in culture medium with or without test agents for 48 h. Duplicates of each treatment were performed in each of three experiments using tissue from a different female. Both 17beta-estradiol and testosterone were measured in aliquots of culture medium by validated radioimmunoassay procedures. Dose-response relationships of individual agents were characterized over a 6-log concentration range (1 X 10(-2) to 1 X 10(4) ppb). Both DDE and methoxychlor, tested individually, produced a dose-dependent decrease in testosterone levels. 17beta-Estradiol levels were unaffected. Mixtures of the agents were tested at all concentration combinations of 0.01, 1, 100, and 10,000 ppb in culture medium. Statistical tests indicated that of 16 dose combinations tested, 15 were antagonistic, and only 1 was additive based on the Loewe additivity model of no interaction. These results imply that methoxychlor and DDE inhibit testosterone production by different mechanisms in bass ovaries.

Animals↗
PubMed1983

Methoxychlor residues in milk of cattle treated with Marlate 50 insecticide as a dermal spray.

Lactating Holstein cattle were treated twice at an interval of 14 days with methoxychlor (Marlate 50 insecticide) as a 0, .25, or .50% dermal spray, with 2 quarts of spray mix applied to each animal. Residues of methoxychlor in whole milk were highest on the 1st or 2nd day after treatment and, when expressed as part per million equivalent in milk fat, were as high as 2.0 and 3.0 ppm in samples from the low and high dosage sprays. Residues in milk dropped rapidly after residues were at most only slightly above the sensitivity limit (.005 ppm in whole milk) of the analytical method. Applicative specifications for Marlate 50 insecticide use on lactating dairy cattle might result in violative methoxychlor residues in milk during the first 1 to 3 days after treatment.

Administration, Topical↗
PubMed1975

Collaborative study of a method for the analysis of dry methoxychlor formulations.

A collaborative study has been completed on a method for determining methoxychlor content in dry formulations. The method is based on a total halogen determination plus a selective, qualitative thin lay chromatographic (TLC) measurement to establish the p,p'-methoxychlor is the primary halogen-containing organic species present in the formulation. After extraction of the sample with toluene, the toluene solution of methoxychlor is treated with sodium biphenyl to convert all halogen to the halide. The halide is then extracted with a solution of nitric acid and titrated with silver nitrate according to the Volhard procedure or potentiometrically, using a pH meter assembly. Based on the results obtained from 7 collaborators, the standard deviation of the method is about 0.48% at the 50% level. The qualitative TLC measurement is made on an aliquot of the initial toluene extract, using a selective halogen detection system. The method has been adopted as official first action.

Chromatography, Thin Layer↗
PubMed1996

Ring hydroxylation of [o-3H]methoxychlor as a probe for liver microsomal CYP2B activity: potential for in vivo CYP2B assay.

An in vitro radiometric assay selective for inducible CYP2B activity is described. The assay is based on the quantification of 3H2O release that occurs during o-ring hydroxylation of [o-3H]methoxychlor by liver microsomes in the presence of NADPH. 3H2O is isolated by removing > 99.9% of the parent compound and organic metabolites by facile charcoal extraction and filtration. There was no evidence for an NIH shift during ring hydroxylation, and there was little or no isotope effect. Selectivity for CYP2B was demonstrated using liver microsomes prepared from rats and mice treated with inducers of different CYP isoforms. Ring hydroxylation of [o-3H]methoxychlor was elevated 11.4-fold over control values in liver microsomes from male rats treated with phenobarbital. With mice, phenobarbital treatment elevated liver microsomal ring hydroxylation 7.1-fold. Clofibrate, 3-methylcholanthrene, or beta-naphthoflavone treatment of male rats or pyridine treatment of female rats did not elevate liver microsomal ring-hydroxylase activity, indicating that CYP4A, 1A, and 2E1 do not support this reaction. In female rats, dexamethasone and pregnenolone-16 alpha-carbonitrile treatment elevated ring hydroxylation up to 5.5- and 3.2-fold, respectively, an activity that may be attributed to CYP2B induction in those animals. Incubation of liver microsomes from phenobarbital-treated males with monospecific anti-CYP2B monoclonal antibodies (Mab) inhibited ring-hydroxylase activity up to 86%, demonstrating predominantly CYP2B-mediated catalysis. An 86% inhibition by these Mabs was also observed using liver microsomes from male mice treated with phenobarbital, indicating the assay is not limited to rats. The CYP2B mechanism-based inhibitor orphenadrine caused a 76% decline in activity, providing further evidence for CYP2B involvement. Unlike other CYP2B-selective assays, this method may be readily adapted to in vivo studies, by measuring urinary excretion of 3H2O as an indication of total body CYP2B activity.

Animals↗
PubMed1998

Inhibition of androgen receptor-dependent transcriptional activity by DDT isomers and methoxychlor in HepG2 human hepatoma cells.

Recent reports have raised new concerns that chemicals in our environment may disrupt normal reproduction and development through inhibition of androgen receptor function. This heightened concern has also increased our need for methods that allow us to characterize chemical interaction with the androgen receptor. In this report we describe an androgen receptor assay that utilizes the HepG2 human hepatoma cell line transiently transfected with the human androgen receptor and an androgen-responsive reporter. We used this assay to characterize the interaction with the androgen receptor of several steroidal and nonsteroidal chemicals, including isomers of DDT and methoxychlor. Chemicals were tested either in the absence (for determining agonist activity) or presence of 10(-7) M dihydrotestosterone (for determining antagonist activity). Testosterone and dihydrotestosterone were equally potent agonists in this assay. Estradiol and progesterone displayed partial agonist/antagonist activity. Flutamide was a complete agonist, whereas its hydroxylated metabolite, hydroxyflutamide, only partially antagonized and displayed some agonist activity at 10(-6) M and above. o,p'-DDT, o,p'-DDE, o,p'-DDD, p,p'-DDT, p,p'-DDE, and p, p'-DDD all behaved as antagonists at concentrations above 10(-6) M. p,p'-DDE also showed some agonist activity at 10(-5) M. Methoxychlor was only weakly antagonistic while its hydroxylated metabolite, HPTE, was approximately 10-fold more potent. Our results demonstrate that the HepG2 assay is a sensitive and specific method for detecting chemical interaction with the androgen receptor. This reporter gene assay, which we have used to characterize interaction with both the estrogen and androgen receptors, coupled with more extensive in vivo studies, should be useful for determining the role of multiple steroid receptors in the mechanism of action of endocrine active chemicals.

Androgen Antagonists↗
PubMed2000

Possible estrogenic and/or antiandrogenic effects of methoxychlor on prolactin release in male rats.

Methoxychlor (MTX) is a pesticide currently used as a substitute for dichloro-diphenyl-trichloroethane (DDT). This organochloride insecticide has some estrogenic properties, and may modify the feedback mechanisms of steroids on the hypothalamus and pituitary. This work was undertaken to explore the possible effects of MTX on the episodic prolactin release and to analyze whether these effects are mediated by dopamine (DA), luteinizing hormone (LH), and/or testosterone. Adult male Sprague-Dawley rats were administered 25 mg/kg/day of MTX in sesame oil for 30 days. Control animals received vehicle only. The episodic prolactin release and plasma testosterone levels were measured as well as the dopamine (DA) content in the median eminence (ME) and in the anterior (AH), mediobasal (MBH), and posterior (PH) hypothalamus. The mean serum prolactin levels and absolute pulse amplitude of the hormone increased after the xenobiotic administration, whereas its relative pulse amplitude diminished. The frequency and duration of prolactin peaks and its half-life were not modified by the treatment with the pesticide. On the other hand, methoxychlor decreased the DA content in ME, increased it in AH, and did not change it in MBH or PH. MTX decreased plasma levels of LH and testosterone compared with controls. These data suggest estrogenic and antiandrogenic effects of MTX on the episodic prolactin secretion; the changes observed in prolactin release could be explained, at least in part, by some of the changes of DA at the hypothalamus and of LH at the pituitary, but not by changes of testosterone at the testicular level.

Androgen Antagonists↗
PubMed1982

Altered imprinting of rat liver monoamine oxidase by o, p'-DDT and methoxychlor.

Neonatal administration of o,p'-DDT [1, 1, 1-trichloro-2-(o-chlorophenyl-2-(chlorophenyl)ethane] or methoxychlor resulted in elevated levels of sex-differentiated hepatic monoamine oxidase activities in adult rats, but not in prepubertal animals. Exposure to these hormonally active xenobiotics may have changed the brain hormone environment during the critical period of development, resulting in endocrine alterations that were reflected by latent but permanent increases in hepatic monoamine oxidase activities, i.e. "altered imprinting". Hepatic glutathione S-transferases and cytochrome P-450 content also underwent sex differentiation, but neonatal treatment with o,p'-DDT or methoxychlor did not alter levels in adult rats. However, glutathione S-transferase activities and cytochrome P-450 content were higher in prepubertal animals treated neonatally with o,p'-DDT. In contrast to monoamine oxidase, effects on glutathione S-transferase activities and cytochrome P-450 content were attributed to induction by these xenobiotics.

Animals↗
PubMed1994

Effects of methoxychlor on skin tumor development.

Organochlorine pesticides increase the incidence of liver cancer through a multistage process involving tumor promotion. Mirex, an organochlorine pesticide has been shown to be a tumor promoter in mouse skin. In the present study, the effects of methoxychlor, a commonly used organochlorine pesticide, on the development of papillomas in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin and induction of mouse epidermal ornithine decarboxylase (ODC) activity were investigated and compared with 12-O-tetradecanoylphorbol-13-acetate (TPA), a well-known tumor promoter. Methoxychlor neither caused tumor development nor induced epidermal ODC activity. However, TPA resulted in 100% tumor incidence and 8.8 tumors per mouse after 20 weeks of promotion, and induced epidermal ODC activity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2004

Enantioselective recognition of mono-demethylated methoxychlor metabolites by the estrogen receptor.

Metabolites of methoxychlor such as 2-(p-hydroxyphenyl)-2-(p-methoxyphenyl)-1,1,1-trichloroethane (mono-OH-MXC) and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (bis-OH-MXC), have estrogenic activity. Mono-OH-MXC is a chiral compound in which the carbon atom bridging two benzene rings is the chiral centre. In previous studies the estrogenic activity of racemic mono-OH-MXC has been measured, and the activity of each enantiomer of this compound has not yet been elucidated. In this study, we evaluated the estrogen receptor-binding activity of each enantiomer of mono-OH-MXC to clarify the enantioselective recognition by the estrogen receptor. (S)-mono-OH-MXC showed 3-fold higher binding activity than that of the (R) enantiomer. The activity of bis-OH-MXC was only 1.7-fold higher than that of (S)-mono-OH-MXC. This result suggests that the one hydroxy group and the orientation of the CCl3 group of mono- and bis-OH-MXCs are important for the interaction with the estrogen receptor. The result also points out the estrogenic activity of methoxychlor after metabolic activation in vivo, which predominantly produces the (S)-mono-OH-MXC, may be higher than estimated from the in vitro activity of racemic mixtures.

Estradiol↗
PubMed2004

Oxidative dechlorination of methoxychlor by ligninolytic enzymes from white-rot fungi.

Ligninolytic enzymes, manganese peroxidase (MnP), laccase, and lignin peroxidase (LiP), from white-rot fungi were used in an attempt to treat methoxychlor (MC), a chemical widely used as a pesticide. MnP and laccase in the presence of Tween 80 and 1-hydroxybenzotriazole (HBT), respectively, and LiP were found to degrade MC, and MnP-Tween 80 decreased MC levels by about 65% after a 24-h treatment. MC was converted into methoxychlor olefin (MCO) and 4,4'-dimethoxybenzophenone by MnP-Tween 80 or laccase-HBT treatment. These results indicate that ligninolytic enzymes from white-rot fungi can catalyze the oxidative dechlorination of MC. Moreover, a metabolite MCO was also degraded by MnP-Tween 80 or laccase-HBT treatment.

Gas Chromatography-Mass Spectrometry↗
PubMed1984

Effect of methoxychlor on reproductive systems of the rat.

Methoxychlor ( MeOCL ), a chlorinated hydrocarbon pesticide, was administered by oral gavage for 70 days to male and 14 days to female rats at dose levels of 100 and 200 mg/kg/day of body weight. Methoxychlor inhibited spermatogenesis in the males and folliculogenesis in female rats. The sustentacular (Sertoli) cells showed degenerative fatty changes as a result of which blood-testis barrier could have been affected. Degenerative changes of the spermatogonia and the spermatocytes and transformation of some of these cells into polynucleated and binucleate cells were observed. Myelin figures and degenerate mitochondria were observed in the binucleate cells at the ultrastructural level. Some of the seminiferous tubules were devoid of all cellular elements with the exception of spermatogonia. The epithelium of the ductus epididymis manifested conspicuous cytoplasmic vacuolations , and near the tail, the duct was distended with fluid which compressed the lining epithelium. Atresia of the ovarian follicles was evident with pyknosis and karyorhexis of the granulosa cells.

Animals↗
PubMed2000

[Chlorinated hydrocarbon insecticides(DDT, methoxychlor, HCH etc.)].

Endocrine disrupting properties of organochlorine(chlorinated hydrocarbon) insecticides are reviewed. Physicochemical properties such as water solubility and partition coefficient of the organochlorine insecticides greatly influence their environmental fates. Insolubility in water and high partition coefficient usually enhance the environmental persistence of the compounds. On the endocrine disrupting properties, an important metabolite of p,p'-DDT, p,p'-DDE, is known to exhibit weak anti-androgenic properties. An isomer o,p'-DDT is estrogenic. Metabolites of methoxychlor, mono-demethylated and di-demethylated methoxychlor derivatives, are weakly estrogenic. Their dehydochlorinated product also exhibits estrogenicity. HCH isomers are environmentally persistent compounds, but there is few reports on their endocrine disrupting properties. Some other organochlorine pesticides such as cyclodienes and chlordecone is reported to be estrogenic.

Androgen Antagonists↗
PubMed1997

Initial Steps in the Degradation of Methoxychlor by the White Rot Fungus Phanerochaete chrysosporium.

The white rot fungus Phanerochaete chrysosporium mineralized [ring-(sup14)C]methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl)ethane] and metabolized it to a variety of products. The three most prominent of these were identified as the 1-dechloro derivative 1,1-dichloro-2,2-bis(4-methoxyphenyl)ethane, the 2-hydroxy derivative 2,2,2-trichloro-1,1-bis(4-methoxyphenyl)ethanol, and the 1-dechloro-2-hydroxy derivative 2,2-dichloro-1,1-bis(4-methoxyphenyl)ethanol by comparison of the derivatives with authentic standards in chromatographic and mass spectrometric experiments. In addition, the 1-dechloro-2-hydroxy derivative was identified from its (sup1)H nuclear magnetic resonance spectrum. The 1-dechloro and 2-hydroxy derivatives were both converted to the 1-dechloro-2-hydroxy derivative by the fungus; i.e., there was no requirement that dechlorination precede hydroxylation or vice versa. All three metabolites were mineralized and are therefore likely intermediates in the degradation of methoxychlor by P. chrysosporium.

Journal Article↗
PubMed1997

The effects of methoxychlor on early sea urchin development.

Methoxychlor (MXC) is a widely used pesticide which has been found in water sources near agricultural sites. Embryos of aquatic organisms are likely to encounter MXC due to land runoff. The sea urchin embryo (Strongylocentrotus purpuratus) was used as a model system to document the effects of MXC on early development up to the pluteus stage. Fertilized eggs and embryos were exposed to several concentrations (0.1, 1.0, 10, and 100 ppm) of the pesticide in both chronic and acute exposure regimens. With chronic exposure, percentages of embryos completing normal first cleavage decreased with increased concentrations of MXC, and subsequent cleavages became even more irregular in that blastomeres divided asymmetrically and asynchronously. Ten parts per million MXC allowed development through the hatched blastula stage, whereas embryos in 100 ppm MXC did not hatch. In acute exposure trials, fertilized eggs were pulsed (i.e., exposed for brief durations) to MXC for 30, 60, or 90 min. The MXC was then washed out. Recovery of normal development was proportional to the amount and duration of MXC exposure. Development was delayed in embryos exposed to 100 ppm MXC for 30 or 60 min. The embryos exposed to 100 ppm MXC for 90 min were abnormal as early as the four-cell stage, and by 72 hr more than 90% had abnormal gut development, indicating disruption of gastrulation. These data show that MXC exposure resulted in retardation of cleavage and abnormal gastrulation, basic morphogenetic processes.

Animals↗
PubMed1995

Effects of estrogen, progesterone, and methoxychlor on surgically induced endometriosis in rats.

Endometriosis is a disease of women where endometrial tissue is found growing at ectopic sites. While evidence suggesting a role for the ovarian hormones in endometriosis exists, no complete studies of the roles of estrogen and progesterone have heretofore been performed. Also, if estrogen has a role in the growth and/or maintenance of endometriosis, it is likely that the proestrogenic pesticide, methoxychlor (MXC), might also have such an effect. Sixty rats underwent surgery on Day 0 to induce endometriosis. On Day 21, all rats were ovariectomized. During surgery, the diameters of all endometriotic implants (which were fully developed) were measured. Starting on Day 21, groups of rats were treated daily, for 3 weeks, with (a) vehicle (b) estrone, 1 micrograms/rat, E;(c) progesterone, 2 mg/rat, P; (d) E + P, 1 micrograms + 2 mg; (e) MXC, 250 mg/kg; or (f) MXC + P, 250 mg/kg + 2 mg/rat. On Day 42, all rats were killed, and the diameters of all endometriotic sites were measured. While no differences in diameter were found across groups prior to ovariectomy, ovariectomy plus treatment altered the growth of endometriosis tissue. Progesterone and vehicle treatments produced results that were identical: regression of endometriotic sites. Both estrogen and MXC treatments maintained endometriotic site size at a level greater than that in the vehicle-treated group. The combination of progesterone with either estrone or MXC did not alter the effect of either chemical. We conclude that while estrogen promotes the growth of endometriosis, progesterone either produces regression or fails to maintain the sites. MXC, at a relatively high dose, supports the development of endometriosis. Concurrent progesterone treatment does not modulate the effects of estrone or MXC. These results suggest that exposure of women to high doses of MXC may exacerbate the development of endometriosis or contribute to its recurrence.

Animals↗
PubMed1997

The effects of perinatal/juvenile methoxychlor exposure on adult rat nervous, immune, and reproductive system function.

In order to address data gaps identified by the NAS report Pesticides in the Diets of Infants and Children, a study was performed using methoxychlor (MXC). Female rats were gavaged with MXC at 0, 5, 50, or 150 mg/kg/day for the week before and the week after birth, whereupon the pups were directly dosed with MXC from postnatal day (pnd) 7. Some dams were killed pnd7 and milk and plasma were assayed for MXC and metabolites. For one cohort of juveniles, treatment stopped at pnd21; a modified functional observational battery was used to assess neurobehavioral changes. Other cohorts of juveniles were dosed until pnd42 and evaluated for changes to the immune system and for reproductive toxicity. Dose-dependent amounts of MXC and metabolites were present in milk and plasma of dams and pups. The high dose of MXC reduced litter size by approximately 17%. Ano-genital distance was unchanged, although vaginal opening was accelerated in all treated groups, and male prepuce separation was delayed at the middle and high doses by 8 and 34 days, respectively. In the neurobehavioral evaluation, high-dose males were more excitable, but other changes were inconsistent and insubstantial. A decrease in the antibody plaque-forming cell response was seen in males only. Adult estrous cyclicity was disrupted at 50 and 150 MXC, doses which also showed reduced rates of pregnancy and delivery. Uterine weights (corrected for pregnancy) were reduced in all treated pregnant females. High-dose males impregnated fewer untreated females; epididymal sperm count and testis weight were reduced at the high, or top two, doses, respectively. All groups of treated females showed uterine dysplasias and less mammary alveolar development; estrous levels of follicle stimulating hormone were lower in all treated groups, and estrus progesterone levels were lower at 50 and 150 MXC, attributed to fewer corpora lutea secondary to ovulation defects. These data collectively show that the primary adult effects of early exposure to MXC are reproductive, show that 5 mg/kg/day is not a NO(A)EL in rats with this exposure paradigm (based on changes in day of vaginal opening, pubertal ovary weights, adult uterine and seminal vesicle weights, and female hormone data) and imply that the sites of action are both central and peripheral.

Animals↗