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PubMed2002

Thymic atrophy induced by methoxychlor in rat pups.

The effect of Methoxychlor (MXC) on the thymus was examined in rat pups that were delivered from dams receiving MXC at a dietary concentration of 0 or 1500 ppm for a period from pregnancy to lactation. The pups of both sexes were euthanized on postnatal days (PNDs) 7, 14, and 21. Histologically, the thymus showed marked depletion of cortical lymphocytes on PND 7 and also had an increase in lymphophagocytosis in the cortical area on PNDs 14 and 21. Morphometrical analysis disclosed that both cortex and medulla of the thymus from treated pups were reduced in size, but the reduction was more evident in the cortex. A significant increase in transferase-mediated dUTP nick end labeling-positive cells was detected in the cortex area, corresponding to the presence of lymphophagocytosis. Flow cytometric analysis revealed a significant decrease in the double positive (CD3(int)CD4(+)CD8(+)) immature cells on PND 21. These results have suggested that MXC may impair maturation of thymic lymphocytes in rat pups, which results in enhancement of apoptosis leading to thymic atrophy during the postnatal period.

Abnormalities, Drug-Induced↗
PubMed2003

Hepatic CYP1A, 2B, 2C, 2E and 3A regulation by methoxychlor in male and female rats.

The effect on liver cytochrome P450 (CYP) by i.p. injections of methoxychlor (MXC) in corn oil at 0, 100, 150, 200 or 250 mg/kg twice daily for 3 days was investigated in adult male and female Wistar rats. The MXC injection (100 mg/kg b.w.) caused a similar increase of total CYP content in males and females as compared with controls who received the vehicle only. In males, this increase continued up to 250 mg/kg. As to the induction of specific CYP activities, the effect of MXC was found to be sex dependent with three different patterns. Males showed the greatest increases of ethoxy- and methoxyresorufin-O-dealkylase (EROD and MROD, respectively), two CYP1A1/1A2-related activities. On the contrary, females were more responsive than males for pentoxyresorufin-O-dealkylase (PROD) and benzyloxyresorufin-O-dearylase (BROD), two CYP2B-related activities. Finally, p-nitrophenol hydroxylase (PNPH), a CYP2E1-related activity, showed a similar small, although statistically significant, increase for both sexes. As to CYP apoprotein levels, CYP1A1 and CYP2B1/2B2 showed greater increases in females than in males; whereas, interestingly, CYP2E1 induction was higher in males than in females. These results indicate overall that gender modulates CYP expression after MXC injection both qualitatively and quantitatively, and, therefore, this pesticide is not a pure PB inducer. Moreover, the statistically significant increase of CYP3A2 apoprotein expression observed in females and also, to a lower extent, in males, and the decrease of CYP2C11 apoprotein found in males, two sex-related enzymes, may explain the reported endocrine disrupting effect of MXC. The relevance of the different patterns of rat liver CYP induction observed after MXC treatment, in relationship to the speculated endocrine disrupting potential of MXC in humans potentially exposed to this pesticide, needs further investigation.

Animals↗
PubMedDate not supplied

Preimplantation mouse embryo development as a target of the pesticide methoxychlor.

Effects of methoxychlor (MXC) and estradiol-17beta (E) were studied in mouse preimplantation embryos. Pregnant mice received s.c. injections of sesame oil only, 10 microg E, or 0.5 mg purified (95%) MXC on Days 2-4 of pregnancy (plug = Day 1). Another group received a single dose of 2.5 microg E on Day 2 only. Based on the average weight of pregnant females, 10 microg of estradiol was equivalent to 0.33 mg/kg of bw, 2.5 microg of estradiol was equivalent to 0.082 mg/kg of bw, and the 0.5-mg dose of MXC was equivalent to 16.5 mg/kg of bw. All embryos were collected for analyses on Day 4. MXC and both estradiol-17beta doses suppressed embryonic development to blastocyst, decreased embryo cell numbers, and caused abnormal blastocyst formation. The high estradiol-17beta dose significantly increased the percent degenerating embryos and caused a tube-locking effect, with retention of embryos in the oviduct. In contrast to estradiol-17beta, MXC at the dose used in this study did not alter tubal transport of embryos. Also in contrast to estradiol-17beta, MXC increased the percentage of nuclear fragmentation and micronuclei. In preimplantation embryos, MXC and estradiol-17beta both suppressed embryo development. MXC effects were, however, different from those of estradiol-17beta, indicating a difference in mechanism of action, possibly due to cytotoxicity and induction of apoptosis.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Effect of methoxychlor on implantation and embryo development in the mouse.

Methoxychlor (MXC) has been shown to have adverse effects on reproductive functions. However, it has not been fully determined whether the effects of MXC on reproduction are due to its estrogenic or antiestrogenic effects. Therefore, to further elucidate the estrogenic action of this pesticide in the mouse, we studied the effect of MXC on implantation and embryo development. MXC was found to initiate implantation in most delayed implanting mice at 400 microg/g body weight. However, at the higher dose of 800 microg/g body weight, MXC initiated implantation in only 50% of animals and the number of embryos implanting was significantly decreased (P < 0.05). It was determined that MXC inhibited implantation in intact pregnant mice only when given on Day 1 or Day 2 at 800 microg/g but not at lower doses or later in the preimplantation period. Embryonic development and transport were delayed on Days 3 and 4 in these animals. Finally, reciprocal embryo transfers with donor embryos recovered from MXC-treated animals (800 microg/g body weight on Day 1) transferred to untreated recipients resulted in no implantation compared to 79% implantation when donor embryos were treated with vehicle. These data indicate that MXC acts as an estrogen agonist at the level of the uterus and oviduct but as an antiestrogen in the ovary. In addition, MXC appears to alter normal preimplantation embryonic development. These results suggest the need for further studies to assess the mechanism of action of MXC in preimplantation embryos.

Animals↗
PubMedDate not supplied

Decreased superovulation in adult mice following neonatal exposures to technical methoxychlor.

To examine the effects of technical methoxychlor (MXC) on superovulation, neonatal mice received intraperitoneal (i.p.) injections of either sesame oil, 10 micrograms of estradiol 17 beta, or 0.1, 0.5, or 1 mg of technical MXC. At 2 and 4 months, half of the mice received a superovulatory regimen of 10 IU pregnant mare's serum gonadotropin followed by 10 IU human chorionic gonadotropin. The mice were sacrificed 15 to 20 h later, the number of ovulated oocytes were counted, and the ovaries were removed for histology. In the lowest MXC dose, the ovaries appeared normal and at 2 months, ovulated the same number of oocytes as controls. Estradiol or the highest two MXC doses induced ovarian atrophy. Following gonadotropin injections, these ovaries also ovulated oocytes. However, the number of oocytes recovered from experimental mice exhibited a time- and dose-dependent decline, and by 4 months, their number was significantly reduced. Neonatal exposures to MXC reduces ovulatory rates and ovarian functions in adults.

Animals↗
PubMedDate not supplied

Neonatal exposure to technical methoxychlor alters pregnancy outcome in female mice.

This study was designed to determine the ability of female mice who were exposed neonatally to the pesticide methoxychlor (MXC) to mate, ovulate, and become pregnant upon reaching sexual maturity. One-day-old female mice (5 to 8/group) were exposed daily by intraperitoneal (ip) injection for 14 d to either sesame oil or 10 microg estradiol-17beta or 0.1, 0.5 or 1.0 mg MXC suspended in sesame oil. The MXC exposures corresponded to 14 to 71, 68 to 357, or 135 to 714 mg/kg body weight, respectively. Three months later, female mice were placed with proven breeder males and checked daily for vaginal plugs. Mated female mice were sacrificed 18 d after the appearance of a vaginal plug to evaluate pregnancy. Uteri were examined for the presence of living fetuses and/or resorption sites. Ovaries were removed and prepared for histologic evaluation and tabulation of corpora lutea. All mice from all three MXC-treated groups did in fact mate, in comparison with only one of those exposed neonatally to estradiol. Increasing the dose of MXC produced a decreased number of pregnant animals at 18 d following mating. The mean number of live fetuses/litter was reduced in the 0.5 and 1.0 mg MXC-treated groups. Corpora lutea were significantly reduced in ovaries from only the 1.0 mg MXC group and the estradiol group. No effects of treatment were seen at 0.1 mg MXC. It is concluded that neonatal exposure to MXC does not interfere with mating. Instead, significant alterations are seen in initiating and/or maintaining pregnancy. The deleterious effects on pregnancy may be due to the influence of neonatal MXC treatments on the hypothalamic-pituitary-ovarian axis as well as on possible alteration of the uterine environment.

Animals↗
PubMedDate not supplied

Methoxychlor given in the periimplantation period blocks sexual arousal in male mice.

To determine whether pesticide methoxychlor (MXC) alters sexual arousal in male offspring, pregnant ICR mice remained untreated or received daily subcutaneous injections (s.c.) of olive oil, 33.0 mg/kg bw purified (95%) MXC, or 0.33 mg/kg bw estradiol-173 in vehicle on Days 5 to 7 of pregnancy. Live births were recorded in all groups except the estradiol group. At 4 months, untreated or olive oil-treated male offspring exhibited normal sexual arousal. When placed near a plastic partition with an estrus female behind it, these males spent significantly more time near the partition than near a vacant half of the cage and exhibited a sharp increase in plasma testosterone. MXC-exposed males showed no sexual arousal, spent much less time near the partition with an estrus female, and exhibited significantly lower plasma testosterone levels. Exposure to purified MXC close to implantation alters the function of the hypothalamic-pituitary-testicular axis and compromises male sexual behavior in offspring.

Animals↗
PubMedDate not supplied

Ethological methods to study the effects of maternal exposure to estrogenic endocrine disrupters: a study with methoxychlor.

There has been increasing interest, both at the scientific and regulatory level, in the use of ethological methods for evaluating neural effects of endocrine disrupters. We present a series of ethological studies on the effects of maternal exposure to low, environmentally relevant doses (0.02, 0.2, and 2 microg/g mother bw/day) of the estrogenic pesticide methoxychlor (MXC) on behavior. From gestation day 11 to 17, female mice spontaneously drank oil with or without MXC; their maternal behavior was examined from postpartum days 2 to 15. MXC treatment during pregnancy produced slight changes in the expression of maternal behavior: females fed the lower MXC dose spent less time nursing the pups as compared to control dams. Their maternally exposed offspring were subjected to a series of behavioral tests at different ages. Maternal exposure to MXC affected behavioral responses to novelty in both sexes at periadolescence. The onset of male intrasex aggression was delayed in males prenatally exposed to low doses of MXC, since exposed males showed low levels of aggressive interactions during early adolescence but not after they reached adulthood. When adults, MXC-exposed females, but not males showed increased exploration in an unfamiliar open-field. While a sex difference was observed in the control group, with males being significantly more active in the open field than females, prenatal treatment with some MXC doses tended to decrease the sexual dimorphism in activity levels in the novel environment. Ethology, as the evolutionary study of behavior, may provide a framework for integrating a functional perspective (i.e., evolutionary significance) to studies on proximate mechanisms that can account for behavioral alterations induced by developmental exposure to endocrine disrupters.

Animals↗
PubMedDate not supplied

Altered behaviors in male mice, male quail, and salamander larvae following early exposures to the estrogenic pesticide methoxychlor.

Numerous publications show that methoxychlor (MXC), in use today as a DDT substitute, is a reproductive toxicant; it produces deleterious effects on the structure and function of the reproductive organs in exposed species. Exposure of mice (33 mg/kg body weight) to purified (95%) MXC at the time of implantation, or injection, of 5 mg MXC into freshly laid quail eggs prior to artificial incubation, altered sexual arousal and sexual behavior in adult males of both species. When placed near a plastic partition with an estrus female behind it, the MXC-exposed male mice showed no sexual arousal, spent less time near the partition, and exhibited lower testosterone levels. Similarly, adult quail males that were exposed to MXC during incubation showed a lack of sexual interest and copulatory behavior when presented with a receptive female. Some males showed a longer latency period before mounting the female, while others did not show any sexual interest at all. Exposure of salamander embryos to purified MXC at or above 0.3 microM (0.1 mg/l) induced precocial hatching of embryos and reduced the startle response and the distance traveled in response to startle. Exposing hatched larvae to MXC for 3 days also resulted in a blunted startle response. Due to the blunted startle response and decreased avoidance travel, the exposed salamander larvae appear more susceptible to predation and these effects may contribute to amphibian population declines. The results of these studies indicate that developmental exposures to environmental chemicals with hormonal activities produce undesirable behaviors that may affect population dynamics and survivability of exposed species.

Animals↗
PubMedDate not supplied

Cognitive testing (delayed non-match to sample) during oral treatment of female adolescent monkeys with the estrogenic pesticide methoxychlor.

This report presents preliminary data from a study of endocrine disruption in adolescence. A delayed non-match to sample (DNMS) task was used to assess the effects of the endocrine-active agent methoxychlor (MXC; 0, 25, or 50 mg/kg/day oral administration) in adolescent female monkeys 24-36 months of age (n=7-8/group). The testing utilized an automated touchscreen operant system (Cambridge Neuropsychological Test Automated Batteries [CANTAB]) with abstract, trial-unique visual stimuli. Basic performance of the task was established prior to dosing, training with simultaneous presentation of sample and choice stimuli continued during dosing, and delays (1/2, 1 or 2 s) were introduced near the end of the dosing period. The MXC50 group performed more poorly than controls during delay testing at the end of the dosing period, as well early in training with simultaneous presentation. No interaction between treatment group and delay interval was found. No significant differences from controls were observed at the lower dose (MXC25). Thus, MXC at a daily dose of 50 mg/kg appeared to interfere in a general way with performance of this visual discrimination and memory task. Further investigation will be needed to identify the impairment leading to this performance deficit.

Administration, Oral↗
PubMed2004

Methoxychlor-induced alterations in the histological expression of angiogenic factors in pituitary and uterus.

Within the reproductive system, oestrogenic stimulation of uterine and pituitary tissue typically causes a proliferative response accompanied by an angiogenic induction of new blood vessels from existing ones, thereby providing nutrients and oxygen to the growing tissue. The pro-oestrogenic pesticide methoxychlor (MXC), however, has shown a differential effect on proliferative activity. An increase in uterine growth is present, while the pituitary undergoes a decrease in size, even though the effect is accompanied by a characteristic oestrogen-induced elevation in pituitary prolactin concentration. The focus of the current study was whether the observed differences in tissue growth between uterus and pituitary in response to MXC administration were paralleled by a corresponding disparity in the expression of those growth factors (members of the vascular endothelial growth factor (VEGF) and angiopoietin families and their receptors) that are involved in the angiogenic cascade. Ovariectomized adult Sprague-Dawley female rats were administered MXC (0-200 mg/kg, oral) for 1 or 3 weeks. Immunohistochemical staining of uteri and pituitaries was performed under strictly controlled conditions for VEGF and its receptor VEGFR2, Angiopoietin-1 (Ang1) and angiopoietin-2 and their tyrosine kinase receptor Tie2, and platelet endothelial adhesion factor (as an index of vascularity). Image acquisition and densitometric assessments of staining intensity were conducted under blind conditions. The results showed uterine MXC-induced increases in the expression of VEGFR2 and Ang1, changes consistent with a normal proliferative response to oestrogenic stimulation. For VEGF, staining tended to be most pronounced in the stromal region, although there did not appear to be a progressive increase with dose. VEGFR2 expression showed significant dose-related trends in luminal and glandular epithelia by 1 week. Similar effects at 1 week were evident for Ang1 in glandular epithelium. In the anterior pituitary, a dose-related increase in VEGF was present for the 1 and 3 week treatments, and the number of pituitary vessels per unit area was also increased after 3 weeks. The effects indicate that even though the insecticide has not been found to cause an augmentation in pituitary growth, a dose-related rise in the expression of at least one principal angiogenic factor is present that may be associated with an increase in vascular density.

Angiogenic Proteins↗
PubMedDate not supplied

The pesticide methoxychlor given orally during the perinatal/juvenile period, reduced the spermatogenic potential of males as adults by reducing their Sertoli cell number.

Perinatal and juvenile oral treatment of rats with the insecticide, methoxychlor (MXC), reduced testicular size and other reproductive indices including the number of epididymal spermatozoa in those animals as adults 161. The objective was to determine if these males exposed during development had fewer Sertoli cells which might explain these testicular effects. Rat dams were gavaged with MXC at 0, 5, 50, or 150 mg x kg(-1) x day(-1) for the week before and after they gave birth. Resulting male pups (15/group) then were dosed directly from postnatal day 7 to 42. Testes were fixed in Bouin's and in OsO4, embedded in Epon and sectioned at 0.5 microm, stained with toluidine blue, and evaluated stereologically or cut at 20 microm to measure Sertoli cell nuclei with Nomarski optics. Sertoli cell number was calculated as the volume density of the nucleus times the parenchymal weight (90% of testicular weight) divided by the volume of a single Sertoli cell nucleus. Across dose groups, there were no changes in the nuclear volume density, the volume of a single nucleus, or the number of Sertoli cells per g parenchyma. There were highly significant dose-related changes in the volume of Sertoli cell nuclei per testis and the number of Sertoli cells per testis. Reduced testicular weight (r = 0.94) and reduced numbers of epididymal spermatozoa (r = 0.43) were significantly (p < 0.01) correlated to reduced number of Sertoli cells per testis. Hence, perinatal and juvenile oral exposure to MXC can reduce spermatogenic potential of males as adults by reducing their number of Sertoli cells.

Administration, Oral↗
PubMed2004

In vitro metabolism of [14C]methoxychlor in rat, mouse, Japanese quail and rainbow trout in precision-cut liver slices.

1. The in vitro metabolism of [14C]methoxychlor (MXC) has been studied using precision-cut liver slices from the Sprague-Dawley male rat, CD-1 male mouse, WE strain male Japanese quail and juvenile rainbow trout (Oncorhynchus mykiss). The results demonstrated integrated phase I and II metabolism of MXC and species differences in the metabolic profiles were observed. 2. In rat liver slice preparations, MXC was rapidly metabolized to bis-OH-MXC by sequential O-demethylation followed by subsequent O-glucuronidation forming bis-OH-MXC glucuronide. No mono-OH-MXC glucuronide was detected. The doubly conjugated metabolite, bis-OH-MXC 4-O-sulphate 4'-O-glucuronide, was also detected as a rat-specific metabolite. 3. Formation of mono-OH-MXC and its glucuronide was the main metabolic pathway in the mouse and Japanese quail. In contrast to the rat, only minor amounts of bis-OH-MXC glucuronide were detected. A reductively dehalogenated metabolite, dechlorinated mono-OH-MXC glucuronide, was observed only in mouse preparations. 4. In rainbow trout, comparative amounts of both mono- and bis-OH-MXC glucuronide were formed as the major metabolites. Unconjugated forms of these metabolites were detected only as minor products. 5. The different metabolic profiles of MXC observed in the four animal species are possibly due to substrate specificity of contributing CYP450 monooxgenase enzyme(s) in different animal species.

Animals↗
PubMed2005

Comparative in vitro metabolism of the suspected pro-oestrogenic compound, methoxychlor in precision-cut liver slices from male and female rats.

The in vitro metabolism of [14C]methoxychlor (MXC), a suspected pro-oestrogenic compound, by male and female Fischer rats (F344) was compared in precision-cut liver slices. The results demonstrated time-dependent metabolism of MXC with integrated phase I and II reactions, and the sex differences were detected in the metabolic profiles. In liver slices from male rats, MXC was metabolized to bis-demethylated MXC (bis-OH-MXC) by sequential O-demethylation followed by subsequent O-glucuronidation. The doubly conjugated metabolite, bis-OH-MXC 4-O-sulphate 4'-O-glucuronide was additionally produced. In the case of the female rat, the glucuronides of both mono- and bis-OH-MXC were formed as the main metabolites, and the mono-OH-MXC glucuronide appeared to be specific to the female rat. The ratios of bis-/mono-demethylated metabolite, which include the amounts of corresponding conjugates, were approximately 95/5 for the male rats and 40/60 for the female. These results imply that demethylation to the intermediate metabolite, (S)-mono-OH-MXC, is a key step for the sex-dependent metabolism of MXC in the rats. The phase I metabolites produced were extensively conjugated with D-glucuronic acid in both male and female rats.

Animals↗
PubMed2000

Estradiol and pesticide methoxychlor do not exhibit additivity or synergism in the reproductive tract of adult ovariectomized mice.

The pesticide methoxychlor (MXC) is a DDT substitute that exhibits estrogenic activities in different animals. To determine whether there is synergism between purified MXC and a natural estrogen, ovariectomized adult mice received 3 daily intraperitoneal doses of either 2.5 or 25 ng estradiol-17beta or 0.125, 0.25, or 0.5 mg MXC administered separately or in combination. The mice were sacrificed on d 4. Reproductive tracts were excised, weighed, and one uterine horn was flushed with phosphate-buffered saline, with the fluid electrophoresed on a one-dimensional sodium dodecyl sulfate polyacrylamide gel to determine albumin content. The remaining uterine horn and vagina were prepared for histology and epithelial height measurements. Estradiol significantly increased reproductive-tract weights. Although both the vaginal and uterine epithelial heights increased in mice treated with combined chemicals when compared to controls, the organ histology did not show increased stimulation. Albumin content was significantly elevated only in the estradiol group. The present data do not suggest that either synergism or additive effects occurred between an estrogen and MXC in the reproductive tracts of ovariectomized adult mice. In fact, combining MXC with estradiol suggests inhibitory effects.

Albumins↗
PubMed2000

Modifying effects of ethinylestradiol but not methoxychlor on N-ethyl-N-nitrosourea-induced uterine carcinogenesis in heterozygous p53-deficient CBA mice.

It is unknown whether endocrine-disrupting chemicals (EDCs) with estrogenic activities have any modifying effects on uterine carcinogenesis. In our previous study, we established a uterine-carcinogenesis model that is useful for detecting tumor-modifying effects of EDCs by the administration of N-ethyl-N-nitrosourea (ENU) to female heterozygous p53-deficient CBA mice [p53 (+/-) mice]. To investigate the effects of ethinylestradiol (EE) and methoxychlor (MXC) on development of ENU-induced uterine tumors, female p53 (+/-) mice and their wild-type littermates [p53 (+/+) mice] received an intraperitoneal injection of 120 mg/kg body weight (bw) of ENU, followed, in Group 1, by no further treatment; in Group 2, by a diet containing 1 ppm EE; in Group 3, by a diet containing 5 ppm EE for 4 weeks and 2.5 ppm EE thereafter; and in Group 4, by a diet containing 2000 ppm MXC for 26 weeks. Uterine proliferative lesions that were induced were composed of both endometrial-stromal and epithelial-cell types. Endometrial stromal sarcomas were induced in p53 (+/-) mice of Groups 1 to 4, and the incidence (87%) in Group 3 was significantly increased compared to Group 1 (47%). Atypical hyperplasias (clear-cell type) of the endometrial gland in p53 (+/-) mice were seen at incidences of 0, 14, 60, and 0% in Groups 1, 2, 3, and 4, respectively, while their incidence in p53 (+/+) mice was 0, 7, 53, and 0%, respectively, with a significant difference between Groups 1 and 3 in both cases. One p53 (+/-) mouse in Group 3 also had an adenocarcinoma consisting of clear cells, and the PCNA labeling indices of the clear-cell atypical hyperplasias, and this endometrial adenocarcinoma, were higher than those of glandular hyperplasias. The present study suggests that 2.5 ppm EE, but not MXC, exerts tumor-promoting effects on stromal and epithelial proliferative lesions of the uteri in p53 (+/-) mice initiated with ENU.

Adenocarcinoma, Clear Cell↗
PubMed2001

Differential gene expression in response to methoxychlor and estradiol through ERalpha, ERbeta, and AR in reproductive tissues of female mice.

The reproductive and developmental effects of 17beta-estradiol (E2) and methoxychlor (MXC) observed in treated rodents appear to be linked to some unique but also overlapping patterns of gene expression. The MXC metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) was previously shown to have selective agonist activity through estrogen receptor alpha (ERalpha) and antagonist activity through ERbeta and androgen receptor (AR). To discover gene families regulated by HPTE and E2, and to characterize similarities and differences in patterns of gene expression induced by these selective ER ligands, we analyzed tissues from mice treated for 3 days with a combined treatment of E2 and HPTE (E2 + HPTE), or the antiandrogen flutamide (FLU). RNA from uteri and ovaries was analyzed with cDNA microarrays and real-time RT-PCR. Results indicate that HPTE and E2 acted similarly to regulate most gene families in the uterus, which expresses predominantly ERalpha. However, in both the uterus and the ovary, there were a few genes that displayed differential patterns of gene regulation by E2 or HPTE treatment, presumably through ERbeta, AR, or other unidentified pathways. In the uterus, progesterone receptor, ERalpha, AR, insulin-like growth factor 1, insulin-like growth factor binding protein 5, and clusterin mRNAs were significantly reduced with both E2 or HPTE treatments, whereas cathepsin B was induced. Conversely, in the ovary, induction of cathepsin B by E2 was reversed after cotreatment with HPTE, and ERbeta expression was induced similarly by HPTE and FLU but not by E2. In addition, E2 uniquely regulated glutathione peroxidase 3, glutathione S-transferase, and cytochrome P450 17alpha-hydroxylase, with no effect of HPTE or FLU treatments. This analysis demonstrated several gene families that appear to be regulated in a ligand-specific pattern, which may explain the unique but overlapping reproductive tissue pathologies following exposure to E2 and MXC.

Animals↗
PubMed2002

Methoxychlor may cause ovarian follicular atresia and proliferation of the ovarian epithelium in the mouse.

Methoxychlor (MXC) is currently used to protect agricultural products from insects. Previous studies show that MXC adversely affects the ovary, but the target cells were not revealed by those studies. Therefore, the purpose of this study was to test the hypothesis that MXC induces ovarian changes by adversely affecting the antral follicles and the ovarian surface epithelium in the mouse. To test this hypothesis, cycling female CD-1 mice (39 days) were dosed with MXC (8, 16, or 32 mg/kg/day), kepone (KPN, 8 mg/kg/day, positive control), or sesame oil (vehicle control) via intraperitoneal injection for 10 or 20 days. Estrous cyclicity was evaluated daily via vaginal lavage. After dosing, ovaries were collected for histological evaluation of follicle numbers, atresia, and surface epithelial height. The results indicate that at the 20-day time point, MXC (32 mg/kg) and KPN (8 mg/kg) increased the percentage of atretic antral follicles (n= 4-9,p<or= 0.001). MXC (32 mg/kg) also increased the height of the ovarian surface epithelium compared with controls (n= 7-10,p<or= 0.045), and KPN increased the percentage of days in estrus (n= 6-10,p<or= 0.0001). These data suggest that MXC and KPN increase antral follicle atresia, MXC increases surface epithelial height, and KPN affects vaginal cytology.

Animals↗