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PubMed2001

Effects of prenatal exposure to low doses of diethylstilbestrol, o,p'DDT, and methoxychlor on postnatal growth and neurobehavioral development in male and female mice.

We examined effects of a wide range of doses of three man-made estrogenic chemicals during fetal life on neurobehavioral changes during early postnatal life in mice. Pregnant mice were fed a 4-log range of o,p'DDT, methoxychlor (MXC), and the drug diethystilbestrol (DES) from gestation days 11 to 17. Offspring were examined for changes in postnatal growth and the development of neuromuscular reflexes. Fetal exposure to the estrogenic chemicals altered the number of live pups per litter, the sex ratio of the litters, the anogenital distance of male and female offspring at birth (a bioassay for fetal androgen action), and the body weight of offspring at birth and during the first 5 days of postnatal life. In most cases, however, the dose-response relationships were complex (non-monotonic), with effects at the highest dose examined being opposite to effects seen at lower doses. The two markers of neurobehavioral development, righting and cliff avoidance reflexes, were not sensitive indicators of prenatal estrogen exposure. Only maternal exposure to the lowest MXC dose produced an increase in reactivity in righting and cliff avoidance tests in offspring.

Animals↗
PubMed1995

Methoxychlor regulates rat uterine estrogen-induced protein.

Methoxychlor (MXC), a proestrogenic pesticide, has adverse effects on fertility and uterine function in rodents. MXC is converted to an estrogenic substance, 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which binds to the estrogen receptor. We examined the similarities in mechanism between MXC (500 mg/kg) and estrogen (10 micrograms/rat) actions using the estrogen-induced protein, IP, also known as creatine kinase. Immature, female rats were treated with MXC or estradiol (E2). Concurrent treatment included actinomycin D (100 micrograms), cycloheximide (100 micrograms), or progesterone (0.5 mg). Uterine proteins were labeled in vitro with 3H for treated rats and with 14C for controls. The uteri were combined, cytosol was isolated, non-denaturing (ND) gels were run, and dpm/gel slice were plotted. In a follow-up study, labeled cytosols from MXC- and E2-treated rats were immunoprecipitated with a monoclonal antibody to creatine kinase. The immunoprecipitate was run on SDS gels. The data show that both MXC and E2 treatments result in ND gels with peaks in (a) induced protein and (b) the 3H/14C ratio, in the same position. The induction of IP by MXC is time- and dose-dependent. Concurrent treatment with MXC plus actinomycin D or cycloheximide blocked IP synthesis, a result parallel to E2 action signifying the necessity of RNA and protein synthesis for IP induction. Progesterone did not block either MXC or E2 induction of IP synthesis. Immunoprecipitation of creatine kinase revealed a single peak at a molecular weight of approximately 49,000. SDS gels of cytosol after MXC or E2 treatment also yielded protein and ratio peaks at molecular weights of approximately 49,000. This estimate is near the published estimated molecular weight of creatine kinase of 46,000. We conclude that MXC action parallels that of estradiol on the induction and regulation of the estrogen-induced protein in immature rat uterus.

Animals↗
PubMed2002

The pesticide methoxychlor disrupts the fusion of myoblasts into myotubes in skeletal muscle cell culture.

We studied the effect of the estrogenic pesticide methoxychlor (MXC) on skeletal muscle development using C2C12 muscle cell culture. Various concentrations of MXC or beta-estradiol (E) were added to the culture media. MXC (100 microM) disrupted myoblast fusion into myotubes, but 10 microM MXC or 10 microM E had no effect. Correlated with the diminished size of the myotubes, the clustering of acetylcholine receptors (AChRs) was inhibited by 100 microM MXC, but not by 10 microM MXC or 10 microM E. However, since clusters of AChR receptors did form, the postsynaptic clustering mechanism remained intact. Since E did not disrupt myoblast fusion into myotubes or the clustering of AChRs, we conclude that the abnormality induced by MXC is mediated by a mechanism of action that is independent of E. We believe this to be the first demonstration that MXC induces abnormal effects in the process of muscle development in skeletal muscle cell culture.

Animals↗
PubMed2002

The hidden effect of estrogenic/antiandrogenic methoxychlor on spermatogenesis.

Perinatal and juvenile oral treatment of rats with methoxychlor (MXC) only during development reduces testicular size and Sertoli cell number in those animals as adults. The objectives were to determine if MXC administered orally reduces numbers of spermatogonia and daily sperm production that parallel reduction in Sertoli cell number and if germ cell degeneration rate or function of individual Sertoli cells was also affected. Rat dams were gavaged with MXC at 0, 5, 50, or 150 mg/kg/day for the week before and after they gave birth. Resulting male pups (14-16 per group) then were dosed directly from postnatal day 7 to 42. Testes were fixed in Bouin's fixative, postfixed in osmium tetroxide, and embedded in Epon. Sections of 0.5 and 20 microm were evaluated stereologically. Across dose groups, body weight was not affected, but testicular weight was significantly reduced in a dose-dependent fashion. Spermatogenic potential based on number of spermatogonia and number of spermatids per testis was significantly reduced by treatment. There was no adverse effect on daily sperm production per gram of parenchyma based on spermatids; however, the number of spermatogonia per gram was reduced. The ratio of spermatid number per spermatogonia was higher in the MXC-treated groups. This difference indicated that the testis can compensate for the treatment-induced reduction in number of spermatogonia by reducing degeneration of their progeny. However, the reduced number of Sertoli cells prevented the compensation from recovering the daily sperm production per testis totally. Given that endocrine disruptors like MXC can induce compensation during spermatogenesis, it may reduce the ability of the testis to compensate during subsequent exposures.

Animals↗
PubMed2002

Uterine responsiveness to estradiol and DNA methylation are altered by fetal exposure to diethylstilbestrol and methoxychlor in CD-1 mice: effects of low versus high doses.

We examined the effects on female CD-1 mice of fetal exposure to low doses of the drug diethylstilbestrol (DES) (0.1 microg/kg/day) and the insecticide methoxychlor (MXC) (10 microg/kg/day) as well as 1000-fold higher doses: 100 microg/kg/day DES and 10,000 microg/kg/day MXC. Pregnant females were administered these chemicals on gestation days 12-18. At 7-8 months of age, female offspring were ovariectomized and implanted for 7 days with a Silastic capsule containing estradiol. Relative to controls, females exposed to the 0.1 microg DES dose showed significantly heavier uteri, while females exposed to the 100 microg DES dose showed significantly lighter uteri. Females exposed prenatally to the 10 microg/kg dose of MXC had significantly heavier uteri relative to females exposed to the 10,000 microg/kg dose of MXC, but neither group differed significantly from controls. Liver weight for females exposed to both doses of DES was significantly greater than controls. Using a microarray approach to analyze DNA methylation, an increase in ribosomal DNA (rDNA) methylation was observed. Sequence data and Southern analysis indicate an increase in 18S rDNA and 45S pre-rDNA methylation in uterine samples exposed prenatally to low and high doses of DES. We thus found opposite effects of fetal exposure to a low and a high dose of DES on the uterine response to estradiol (inverted-U dose-response relationship). In contrast, there was a monotonic dose-response relationship found for prenatal DES exposure on both liver weight and ribosomal DNA hypermethylation.

Analysis of Variance↗
PubMed1977

Photochemical transformation of the DDT and methoxychlor degradation products, DDE and DMDE, by sunlight.

DDE and DMDE, degradation products of the pesticides DDT and methoxychlor, rapidly undergo an unusual photoisomerization in solution when exposed to sunlight. The isomerization involves the exchange of a vinyl chlorine and an ortho aromatic hydrogen. Other photoproducts identified were corresponding benzophenones and 1,1-diaryl-2-chloroethylenes. Quantum yields for the reactions were measured and then used to compute sunlight photolysis half-lives for DMDE and DDE. Although both compounds absorb only the short-wavelength ultraviolet component of sunlight, their photolysis was found to be surprisingly rapid. During summer at latitude 40 degrees N, the photolysis half-lives near the surface of a water body are one hour and one day for dissolved DMDE and DDE, respectively. Photolysis of the DDE photoisomers is about an order of magnitude slower than that of DDE, suggesting that they may accumulate under environmental conditions. The DDE photoisomers photocyclize to form chlorinated dibenzofulvene and dichlorofluorenone. Neither DDE nor its photoisomers photoreact in solution to form PCB's. The environmental significance of these results is discussed, and its is suggested that the persistence of DDE in inland surface waters may be related to its tendency to sorb onto sediments and biota where not light is present.

Dichlorodiphenyl Dichloroethylene↗
PubMed1993

Replacement of estrogen by methoxychlor in the artificially-induced decidual cell response in the rat.

The pesticide methoxychlor (MXC) exhibits estrogenic activity although it is not a steroid. Therefore its mode of action may differ from that of estrogen. Here we evaluated the ability of MXC to replace estrogen in the ovariectomized, hormone-treated decidual cell response (DCR) model. Following priming with estrone, ovariectomized rats were treated with estrone plus progesterone, progesterone alone, or progesterone plus various dosage levels of MXC. Within a narrow dose range, MXC can replace estrone and, in combination with progesterone, produce a maximal DCR. In the same manner as that seen with progesterone plus estrone, progesterone plus MXC produced no effect different from progesterone alone at low to intermediate dosages and an inhibition of decidual growth at high doses. The data support the hypothesis that MXC exhibits classical mechanisms of estrogenic activity.

Animals↗
PubMed1986

Effects of low subchronic doses of methoxychlor on the rat hypothalamic-pituitary reproductive axis.

The pesticide methoxychlor (MXC) is known to possess a weak estrogenic action and has been found to have a number of toxic effects on the rodent reproductive system, primarily at the gonadal level. The purpose of this study was to explore the influence of MXC on the pituitary and hypothalamic components of the male reproductive system at dose levels that were without detectable testicular effects. At 21 days, male Long-Evans rats were gavaged daily with 25 or 50 mg/kg MXC in corn oil. Controls received vehicle only. After 8 weeks of dosing, no significant changes were seen in serum LH, FSH, or prolactin, nor in the pituitary concentrations of LH or FSH. Pituitary prolactin was elevated for both doses, and pituitary fragments perifused in vitro released more prolactin than did controls. The concentration of gonadotropin-releasing hormone (GnRH) was higher in the mediobasal hypothalamus, but only for the 50-mg/kg group. At this dose, there was a corresponding increase in the KCl-stimulated release of GnRH. The data suggest that previously reported reproductive effects of MXC may be mediated, at least in part, through an elevation in prolactin concentration and release, which in turn is able to influence hypothalamic levels of GnRH. This prolactinemic effect may well represent an early component of the adverse action of MXC on the reproductive system.

Administration, Oral↗
PubMed1987

Methoxychlor affects the decidual cell response of the uterus but not other progestational parameters in female rats.

The pesticide methoxychlor (MXC) is a proestrogen which is metabolized to a compound that has been shown to exhibit estrogenic activity in vivo and in vitro. Following long-term exposure of female rats to MXC, fertility is reduced and fetotoxicity is evident. However, the effects of MXC on several aspects of maternal reproductive physiology, including the decidual cell response (DCR), ovarian weight, serum progesterone levels, and corpora lutea maintenance, have not been previously described. In the present study, the ability of MXC to interfere with progestational events essential for implantation and the maintenance of pregnancy in the rat was investigated. MXC was administered to pseudopregnant rats, decidualization was induced on Day 4, and the DCR and related parameters were evaluated following euthanasia on Day 9. DCR induction during estrone administration served as a positive control. MXC inhibited decidualization in a dose-dependent manner: while 100 mg/kg/day had no effect, doses of 200, 300, 400, and 500 mg/kg/day produced incremental inhibition of the response. No effects of MXC on ovarian weight, serum progesterone levels, or number of corpora lutea were observed. Estrone also inhibited the DCR in a dose-dependent manner. The data suggest that the anti-fertility effect of MXC is mediated by a suppression of decidualization and that such suppression, which is characteristic of estrogenic compounds, is a direct uterine effect. In the DCR model system, the estrogenic activity of MXC is 1/20,000 times the activity of estrone.

Animals↗
PubMed1989

Antifertility effect of methoxychlor in female rats: dose- and time-dependent blockade of pregnancy.

Long-term exposure to methoxychlor (MXC), an estrogenic pesticide, produces infertility in rats, and short-term exposure blocks the decidual cell response (DCR). To address the short-term effects of MXC on fertility, the differential effects of MXC dosage and timing of administration (relative to implantation) on several gestational parameters were investigated. When MXC was administered during early pregnancy (Days 1-8), a dose-dependent decline in implantations and uterine weight was seen with no effect on ovarian weight or corpora lutea; MXC reduced serum progesterone at all doses. Preimplantation administration of MXC (Days 1-3 of pregnancy) produced a decline in implantations and uterine weight, while postimplantation dosing (Days 4-8 of pregnancy) increased resorptions to 100%, decreased uterine weight, and reduced serum progesterone without affecting the number of implantations, ovarian weight, or number of corpora lutea. The DCR of pseudopregnancy was inhibited by 500 mg/kg/day MXC when administered either pre- or postimplantation, but 200 mg/kg/day was without effect in either regimen. When hormonally primed, long-term ovariectomized rats were exposed to doses of 500 mg/kg/day, MXC blocked the induced DCR seen in controls. The data show that short-term MXC dosing during early pregnancy produces a dose-related infertility. The bloickade of pregnancy by the preimplantation administration of MXC may be mediated by a direct effect on preimplantation uterine development. The fetal resorption seen following postimplantation dosing is considered a manifestation of both reduced serum progesterone and the direct disruption of normal decidual development by MXC.

Animals↗
PubMed1990

Methoxychlor accelerates embryo transport through the rat reproductive tract.

The estrogenic pesticide methoxychlor (MXC) is known to reduce implantation, and, in our previous work, this reduction has been attributed to a direct effect on uterine function. The present study was designed to investigate the effect of MXC on embryo transport rate, another phenomenon that is vulnerable to estrogenic effects. MXC was administered by gavage, at 0, 100, 200, and 500 mg/kg/day, to groups of rats on Days 1-3 of pregnancy (Day 0 = sperm positive), and the distribution of embryos in the oviducts and uteri of animals was assessed at five time intervals prior to implantation. No effect of MXC was detected by the afternoon of Day 1. On Days 2 and 3 of pregnancy, 200 and 500 mg/kg/day MXC were found to accelerate embryo transport into the uterus; the 500 mg/kg/day dosage also reduced the total number of embryos recovered from the tract. On the third day, 100 mg/kg/day MXC also accelerated embryo transport to the uterus and 200 mg/kg/day MXC reduced total embryo recovery. Until the afternoon of Day 3, most control embryos remained in the oviduct. These data demonstrate that MXC produces a dose-dependent acceleration of embryo transport through the female reproductive tract. When compared with previous work, the current data indicate that such an acceleration is the primary cause of MXC-induced preimplantation embryonic loss when exposure occurs after fertilization.

Animals↗
PubMed1976

Mutagenicity and purative carcinogenicity tests of several polycyclic aromatic compounds associated with impurities of the insecticide methoxychlor.

Several polycyclic hydrocarbons, 3,6-dimethoxy-9,10-bis(p-methoxyphenyl)-phenathrene, tetrakis(p-methoxyphenylyethylene and 3,6,11,14-tetramethoxydibenzo(g,p)chrysene, which are associated as impurities in commerical samples of the insecticide methoxychlor, have been tested in the Ames mutagenicity test with strains of Salmonella thyphimurium, TA 1535, TA 1537, TA 1538, and TA 98. Activation by liver microsomes induced with either phenobarbitol or Aroclor was examined. The only active compound was 3,6,11,14-tetramethoxydibenzo(g,p)chrysene, mutagenic (0.39 revertants/nmol) tostrain TA 98.

Chrysenes↗
PubMed1988

Effect of ionic contents in saline on depolarizing afterpotential induced by phenothrin and methoxychlor.

1. The depolarizing afterpotential induced by phenothrin and methoxychlor in crayfish giant axons was measured intracellularly. 2. Changes in the K+ ion concentration did not affect the depolarizing afterpotential when evaluated as the membrane potential. 3. Addition of tetrodotoxin or replacement of the Cl- ions by OAc- ions or of the Na+ ions by choline ions reduced the depolarizing afterpotential and the action potential. 4. A ratio of the reduction of the depolarizing afterpotential in saline that contained OAc- ions to that of the action potential was similar to that measured in the saline containing tetrodotoxin. 5. With the increase in the choline concentration, the relative value of the depolarizing afterpotential to that measured before the replacement decreased almost linearly with that of the decrease in the action potential.

Action Potentials↗
PubMed1991

Effects of methoxychlor on the reproductive system of the adult female mouse. 1. Gross and histologic observations.

The purpose of this study is to examine the effects of the pesticide methoxychlor (MXC) on the reproductive system of the adult female mouse. Sexually mature (7- to 8-week) virgin female CD-1 mice were exposed to 1.25, 2.5, or 5.0 mg MXC (50% technical grade) via oral gavage for 5 consecutive days each week for either 2 or 4 weeks. Control groups received either 0.025 mg estradiol-17 beta (E-17 beta) or the sesame oil vehicle for the same time period. Vaginal smears were taken daily, and weights were recorded weekly. Twenty-four hours following the final exposure, animals were sacrificed. Ovaries and reproductive tracts were removed and weighed. One ovary from each animal was prepared for light microscopic evaluation. Results revealed a dose dependency of MXC in inducing persistent vaginal estrus (PVE). Ovaries of MXC-exposed and E-17 beta-exposed animals weighed significantly less than the sesame oil controls. In addition, there was an increase in the number of atretic large follicles in the E-17 beta group and in those mice treated with the two highest doses of MXC, indicating a potential reduction in the immediate fertility of the animal. Thus, this commonly employed pesticide appears to mimic closely those effects on the female reproductive system induced by estrogens.

Animals↗
PubMed1992

Effects of methoxychlor treatment of pregnant mice on female offspring of the treated and subsequent pregnancies.

This study was designed to assess whether exposure to the estrogenic pesticide methoxychlor (MXC) during pregnancy would affect reproductive parameters not only in female offspring exposed prenatally, but also in those of a subsequent litter. Mice were exposed via oral gavage to 7.5, 5.0, or 2.5 mg technical grade MXC (50%) or 0.025 mg estradiol-17 beta (E-17 beta) from days 6 to 15 of pregnancy. Following delivery, female offspring (F1a) were cross-fostered and sacrificed at 8 weeks of age. Mothers exposed during their first pregnancy were allowed to mate again and their second set of offspring (F1b) were similarly evaluated to detect any latent effects from the initial exposure. Mice exposed to 7.5 mg MXC were unable to carry their litters to term. Results revealed a significant increase in the length of gestation of mice exposed to both E-17 beta and 5.0 mg MXC. A larger percentage of atretic follicles appeared in the ovaries of F1a females exposed prenatally to 5.0 mg MXC when compared to controls. Females from the F1b litter displayed a significant advance in time of vaginal opening, an apparent residual effect of MXC from a mother exposed during a previous pregnancy.

Abnormalities, Drug-Induced↗
PubMed1992

Effects of methoxychlor on the reproductive system of the adult female mouse: 2. Ultrastructural observations.

The purpose of this study is to examine the effects of the pesticide methoxychlor (MXC) on the ultrastructural appearance of the different cellular components of the mouse ovary. Sexually mature (7- to 8-week) virgin female CD-1 mice were exposed to 5.0 mg MXC (50% technical grade) via oral gavage for 5 consecutive days each week for 4 weeks. Control groups received either 0.025 mg estradiol-17 beta (E-17 beta) or the sesame oil vehicle for the same time period. Twenty-four hours following the final exposure, animals were sacrificed. Ultrastructural observations revealed increased lipid accumulation in interstitial cells and theca cells of both estradiol-treated and 5.0 mg MXC-treated mice. This would suggest that these cells are unable to synthesize and secrete steroids. Thus, this commonly employed pesticide appears to closely mimic those effects on the female ovary induced by estrogen.

Animals↗
PubMed1993

Effect of methoxychlor on ovarian steroidogenesis: role in early pregnancy loss.

Antifertility properties of the pesticide methoxychlor (MXC) are well documented. Administration of MXC to rats during early pregnancy impairs implantation and reduces serum progesterone. The current study was designed to examine the effect of MXC on ovarian steroidogenesis and to define the mechanism(s) by which the pesticide exerts this effect. Rats were treated with MXC at a range of doses during days 1 to 8 of pregnancy and killed on day 9. Ovaries were incubated to assess the secretion of progesterone, estradiol, and testosterone in vitro. Steroid hormones in medium and serum were measured by radioimmunoassay. Although in vivo treatment with MXC reduced serum progesterone, no effect on the ovarian secretion of progesterone was detected in vitro. Conversely, MXC had no effect on serum estradiol levels (testosterone levels were undetectable in serum), but the incubation of ovaries in vitro revealed a reduction in the rates of ovarian estradiol and testosterone secretion.

Abortion, Spontaneous↗
PubMedDate not supplied

Mechanisms of the stimulation of rat uterine peroxidase activity by methoxychlor.

Methoxychlor (MXC) has adverse effects on fertility and rat uteri via its active metabolite HPTE (2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane). Uterine peroxidase, a marker of estrogen action, was used to probe potential mechanisms of MXC's adverse effects. Specifically, our objective was to compare the regulation of the effects of estrogen and MXC on uterine peroxidase. Immature female rats were treated with MXC (250 mg/kg; gavage) 24 h prior to the measurement of uterine peroxidase activity, with or without concurrent treatment with actinomycin D, cycloheximide, progesterone, or tamoxifen. MXC alone produced an increase in peroxidase activity. The prior and/or concurrent treatment with the compounds listed blocked the MXC-induced stimulation of peroxidase. These data show similarities between the mechanisms of estrogen MXC action. Both estrogen and MXC act to stimulate uterine peroxidase activity via increased RNA and protein synthesis and this stimulation can be blocked by progesterone and tamoxifen.

Animals↗