Two-generation reproduction toxicity study in rats with methoxychlor
Laboratories of Reproductive Toxicology, Toxicology Division, Institute of Environmental Toxicology, Ibaraki, Japan. Congenital Anomalies
(Impact Factor: 1.08).
03/2012; 52(1):28-41. DOI: 10.1111/j.1741-4520.2011.00344.x
A two-generation reproduction toxicity study was conducted in rats with a reference estrogenic pesticide, methoxychlor, to validate the sensitivity and competency of current guidelines recommended by the United States Environmental Protection Agency; Japanese Ministry of Agriculture, Forestry and Fisheries; and Organisation for Economic Co-operation and Development for predicting reproductive toxicity of the test compound based on estrogenic endocrine disrupting effects. Both sexes of SD rats were exposed to methoxychlor in the diet at concentrations of 0, 10, 500 and 1500 ppm for two successive generations. The present study has successfully detected estrogenic activities and reproductive toxicities of methoxychlor, as well as its systemic toxicity. Body weights, body weight gains and food consumption of both sexes of animals were suppressed significantly in the 500 and 1500 ppm groups. Typical reproductive toxicities observed in females of these groups included, but were not limited to, prolonged estrous cycle, reduced fertility, decreased numbers of implantation sites and newborns, decreased ovary weights and/or increased incidences of cystic ovary. Uterine weights of weanlings increased significantly in these groups, suggesting that the sensitivity of this parameter for predicting estrogenic ability of the test compound is comparable to that of the uterotrophic assay. Reproductive toxicities of methoxychlor seemed less potent in males than in females. Methoxychlor delayed preputial separation and significantly reduced sperm counts and reproductive organ weights of males of the 500 and/or 1500 ppm groups; however, most males that failed to impregnate females in the same group showed normal fertility when they were re-mated with untreated females. Neither systemic nor reproductive toxicities appeared in the 10 ppm group.
Available from: Robert Chapin
- "Effects of methoxychlor treatment on female hormone levels are also complicated. When serum was collected from proestrus females whose litter sizes were lower than those in the control group in a two-generation reproduction study with methoxychlor, serum E 2 was significantly decreased at and above 500 ppm (equivalent to 43.5 mg/kg/day), while concentrations of FSH, LH, and progesterone in these females were unchanged up to the highest concentration (Aoyama et al., 2012). This can be interpreted that estrogenic stimuli of methoxychlor and/or HPTE may substitute for estrogen to decrease the endogenous E 2 level. "
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ABSTRACT: Methoxychlor is an organochlorine pesticide having a weak estrogenicity, which is estimated to be approximately 1000- to 14,000-fold less potent to a natural ligand, 17β-estradiol. However, its active metabolite, hydroxyphenyltrichloroethane, has much more potent estrogenic activity and probably acts in the target organs of animals exposed to methoxychlor at least 100 times stronger than the parent compound. A variety of in vivo reproductive toxicity studies have shown that treatment with methoxychlor exerts typical endocrine-disrupting effects manifest as estrogenic effects, such as formation of cystic ovaries resulting in ovulation failures, uterine hypertrophy, hormonal imbalances, atrophy of male sexual organs, and deteriorations of sperm production in rats and/or mice, through which it causes serious reproductive damages in both sexes of animals at sufficient dose levels. However, methoxychlor is not teratogenic. The no-observed-adverse-effect level of methoxychlor among reliable experimental animal studies in terms of the reproductive toxicity is 10ppm (equivalent to 0.600mg/kg/day) in a two-generation reproduction toxicity study.
Available from: ncbi.nlm.nih.gov
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ABSTRACT: O-Demethylation of insecticide methoxychlor is well known as a phase I metabolic reaction in various eukaryotic organisms.
Regarding prokaryotic organisms, however, no individual species involved in such reaction have been specified and characterized
so far. Here we successfully isolated a bacterium that mediates oxidative transformation of methoxychlor, including O-demethylation and dechlorination, from river sediment. The isolate was found to be closely related to Bradyrhizobium elkanii at the 16S rRNA gene sequence level (100% identical). However, based on some differences in the physiological properties
of this bacterium, we determined that it was actually a different species, Bradyrhizobium sp. strain 17-4. The isolate mediated O-demethylation of methoxychlor to yield a monophenolic derivative [Mono-OH; 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane]
as the primary degradation product. The chiral high-performance liquid chromatography (HPLC) analysis revealed that the isolate
possesses high enantioselectivity favoring the formation of (S)-Mono-OH (nearly 100%). Accompanied by the sequential O-demethylation to form the bis-phenolic derivative Bis-OH [1,1,1-trichloro-2,2-bis(4-hydroxyphenyl)ethane], oxidative dechlorination
of the side chain proceeded, and monophenolic carboxylic acid accumulated, followed by the formation of multiple unidentified
polar degradation products. The breakdown proceeded more rapidly when reductively dechlorinated (dichloro-form) methoxychlor
was applied as the initial substrate. The resultant carboxylic acids and polar degradation products are likely further biodegraded
by ubiquitous bacteria. The isolate possibly plays an important role for complete degradation (mineralization) of methoxychlor
by providing the readily biodegradable substrates.
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ABSTRACT: Outbred stocks of rats have been used extensively in biomedical, pharmaceutical and/or toxicological studies as a model of genetically heterogeneous human populations. One of such stocks is the Wistar Hannover GALAS rat. However, the colony of Wistar Hannover GALAS rat has been suspected of keeping a problematic mutation that manifests two distinct spontaneous abnormalities, goiter and dwarfism, which often confuses study results. We have successfully identified the responsible mutation, a guanine to thymine transversion at the acceptor site (3′ end) of intron 6 in the thyroglobulin (Tg) gene (Tgc.749−1G>T), that induces a complete missing of exon 7 from the whole Tg transcript by mating experiments and subsequent molecular analyses. The following observations confirmed that Tgc.749−1G>T/Tgc.749−1G>T homozygotes manifested both dwarfism and goiter, while Tgc.749−1G>T/+ heterozygotes had only a goiter with normal appearance, suggesting that the mutant phenotypes inherit as an autosomal semi-dominant trait. The mutant phenotypes, goiter and dwarfism, mimicked those caused by typical endocrine disrupters attacking the thyroid. Hence a simple and reliable diagnostic methodology has been developed for genomic DNA-based genotyping of animals. The diagnostic methodology reported here would allow users of Wistar Hannover GALAS rats to evaluate their study results precisely by carefully interpreting the data obtained from Tgc.749−1G>T/+ heterozygotes having externally undetectable thyroidal lesions.
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