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The role of metabolism in the estrogenic activity of chlorinated hydrocarbon pesticides was examined. Whether the estrogenic activity in technical grade preparations of the pesticide methoxychlor is due to methoxychlor or to contaminants was also investigated. Identified compounds in technical methoxychlor were examined by an in vitro method to determine whether they are estrogens or proestrogens. This method showed that purified methoxychlor and MDDE, an olefinic derivative of methoxychlor, are proestrogens and that monohydroxymethoxychlor and monohydroxy-MDDE are estrogens. Thus, the estrogenic activity in technical methoxychlor is due to both methoxychlor and contaminants. MDDE is an in vivo metabolite of methoxychlor, and the mono- and bishydroxy derivatives of methoxychlor and MDDE are metabolites of methoxychlor and MDDE, respectively. These metabolites exhibited in vitro estrogenic activity in the following order of potency: bis-OH-MDDE greater than bis-OH-methoxychlor greater than mono-OH-MDDE greater than mono-OH-methoxychlor. A similar order of potency was observed in vivo, demonstrating that metabolites of methoxychlor are potent estrogens. In addition to phenolic products, hepatic monooxygenases metabolize methoxychlor and MDDE to reactive intermediates that bind covalently to microsomal proteins. Further studies are needed to determine the factors controlling the two pathways of methoxychlor metabolism and determine whether covalent binding is associated with cellular and organ toxicity.
Cytochrome P-450SCC (P-450 XIA1) from bovine adrenocortical mitochondria was investigated using a suicide substrate: [14C]methoxychlor. [14C]Methoxychlor irreversibly abolished the activity of the side-chain cleavage enzyme for cholesterol (P-450SCC) and the inactivation was prevented in the presence of cholesterol. The binding of [14C]methoxychlor and cytochrome P-450SCC occurred in a molar ratio of 1:1 and the cholesterol-induced difference spectrum of cytochrome P-450SCC was similar with the methoxychlor-induced difference spectrum. [14C]Methoxychlor-binding peptides were purified from tryptic-digested cytochrome P-450SCC modified with [14C]methoxychlor. Determination of the sequence of the amino-acid residues of a [14C]methoxychlor-binding peptide allowed identification of the peptide comprising the amino-terminal amino-acid residues 8 to 28.
Numerous chemicals released into the environment by man are able to disrupt the functioning of the endocrine system by binding to hormonal receptors. Exposure to estrogenic endocrine disruptors during critical periods in fetal life can alter the development of reproductive organs, the neuroendocrine system and subsequent behavior. We present a series of studies on the effects of exposure during fetal life to low, environmentally relevant doses of two pesticides, o,p'DDT and methoxychlor, and of low doses of the synthetic estrogen, diethylstilbestrol on subsequent neuro-behavioral development in house mice. The main findings can be summarized as follows: (1) Mice prenatally exposed to methoxychlor showed changes in reflex development. Exposure to a very low dose of methoxychlor appeared to produce an increased reactivity during early postnatal life. (2) Methoxychlor exposed periadolescent mice showed a decreased reaction time exploring both a novel environment and a novel object. (3) The onset of male intrasex aggression appeared to be delayed in males prenatally exposed to low doses of methoxychlor, since exposed males showed low levels of aggressive interactions during early adolescence but not after they reached adulthood. (4) The rate of depositing urine marks in a novel environment was increased in males prenatally exposed to DES, and also to o,p'DDT and methoxychlor. (5) The proportion of both males and females attacking a same-sex conspecific was increased in mice prenatally exposed to low doses of DES and, marginally, to o,p'DDT. This effect appeared to be related to a decreased latency to attack. However, males prenatally exposed to o,p'DDT displayed a decreased intensity of aggression. The possible implications of perturbing the hormonal milieu during fetal development on the modulation of developmental turnpoints and future behavioral responses are discussed.
Environmental toxicants profoundly affect growth and developmental processes. In the present study, we hypothesized that hypothalamic gonadotropin-releasing hormone (GnRH) neurons, which regulate the reproductive axis, are targets of environmental endocrine disrupting chemicals. Two organochlorine pesticides (methoxychlor and chlorpyrifos) were tested for their effects on GnRH gene expression and biosynthesis in the immortalized hypothalamic GT1-7 cells, which synthesize and secrete GnRH. GT1-7 cells were treated with methoxychlor or chlorpyrifos for 24 h in dose-response experiments, and GnRH gene expression and peptide levels were quantified. In order to examine whether these pesticides affect GnRH biosynthesis through the estrogen receptor (ER), in other experiments their effects were compared to those of estrogen, or they were co-administered with the ER antagonist, ICI 182,780 (ICI). Both methoxychlor and chlorpyrifos had significant effects on GnRH gene transcription and GnRH mRNA levels. These effects were not consistently blocked by ICI, nor did the effects of these pesticides consistently mimic those of estrogen, suggesting a mechanism independent of the ER. Chlorpyrifos and methoxychlor slightly stimulated peptide levels, and this effect was blocked by ICI, suggesting that the ER may mediate effects of pesticides on GnRH release. These results indicate that chlorpyrifos and methoxychlor alter GnRH biosynthesis in this hypothalamic cell line in vitro, suggesting that they may have endocrine disrupting effects on GnRH neurons in vivo.
An assay, employing microsomes prepared from rat liver and a recombinant cell bioassay (RCBA) expressing the human oestrogen receptor (alpha) linked to a reporter gene, was evaluated for the detection of pro-oestrogens in food using methoxychlor and mestranol as model compounds. Bio-activation of the hop phytoestrogen isoxanthohumol to the potent oestrogen 8-prenylnaringenin was also investigated. The oestrogenic potency values for reference standards determined with the RCBA (17beta-oestradiol = 100%) were: methoxychlor 0.0025%, mestranol 1.3%, isoxanthohumol 0.001%, and for their potential respective metabolites were: bishydroxymethoxychlor 0.015%, 17alpha-ethynyl oestradiol 69% and 8-prenylnaringenin 0.4%. Incubation of methoxychlor and mestranol (10 microM) with microsomes prepared from the liver of rats treated with Aroclor 1254 significantly increased (p < 0.001) their oestrogenic potency from 0.0021 and 2.4% to 0.015 and 8.3%, respectively. In contrast, the potency of the hop phytoestrogen isoxanthohumol was unchanged. Metabolites were identified by UV-HPLC-MS/MS as monohydroxy methoxychlor and HPTE from methoxychlor, and the major metabolite of mestranol was 17alpha-ethynyl oestradiol. There was no evidence for the metabolism of isoxanthohumol. Mestranol was also activated by microsomes induced with saline (control), beta-napthoflavone, 3-methylcholantherene, isoniazid or pregnenolone-16alpha-carbonitrile, but not phenobarbitone. These studies demonstrate the principle for use of a binary assay system for the detection of pro-oestrogens and indicate the potential value for risk assessment of endocrine disrupting chemicals.