Cytochrome P450 Catalyzed Covalent Binding of Methoxychlor to Rat Hepatic, Microsomal Iodothyronine 5′-Monodeiodinase, Type I: Does Exposure to Methoxychlor Disrupt Thyroid Hormone Metabolism?

doi:10.1006/abbi.1995.1479

Archives of Biochemistry and Biophysics

Volume 322, Issue 2, 1 October 1995, Pages 390-394

https://doi.org/10.1006/abbi.1995.1479 Get rights and content

Abstract

The insecticide methoxychlor is estrogenic in birds and mammals and interferes with sexual development and reproduction, but it is not known whether this toxicity is due solely to its estrogenicity. We now have found that during hepatic, microsomal metabolism of [ring-¹⁴C]- or [³H-OCH₃]methoxychlor, their metabolite primarily binds to iodothyronine 5′-monodeiodinase, type I (5′-ID1). The purified, radiolabeled protein reacted with antibodies against protein disulfide isomerase, isoform Q5, which is highly homologous to 5′-ID1. Sequencing of the radiolabeled tryptic peptide indicated that methoxychlor bound to cysteine 372 or 375 or to lysine 376 of 5′-ID1. Treatment of rats with methoxychlor for 4 days decreased hepatic, microsomal 5′-ID1 activity from 2.94 to 2.20 nmol/min-mg prot (P < 0.02). Since 5′-ID1 catalyzes thyroxine conversion to the biologically active triiodothyronine, these data suggest that methoxychlor may interfere with thyroid hormone metabolism. This may be an additional factor in its environmental toxicity.

References (0)

Cited by (37)

Fathoming the link between anthropogenic chemical contamination and thyroid cancer
2020, Critical Reviews in Oncology/Hematology
Citation Excerpt :
For example, rat studies demonstrated that DDT exerted inhibitory effect on the sodium iodine symporter, therefore impairing iodine uptake (Yaglova and Yaglov, 2015). By contrast, heptachlor has been specifically shown to inhibit thyroperoxidase and therefore thyroid hormone biosynthesis (Song et al., 2012), while methoxychlor was found to decrease hepatic deiodinase activity, therefore affecting thyroid hormone clearance (Zhou et al., 1995). To date, evidence of thyroid disrupting activity is available for many heavy metals (Rana, 2014).
Incidence and mortality of thyroid cancer are increasing, thus making mandatory to improve the knowledge of disease etiology. The hypothesis of a role for anthropogenic chemicals is raising wide consideration.
A series of occupational studies revealed that job exposures with high risk of chemical contamination were usually more prone to thyroid cancer development. These include shoe manufacture, preserving industry, building activities, pulp/papermaker industry and the wood processing, agricultural activities, and other work categories characterized by contact with chemicals, such as chemists and pharmacists. However, such epidemiological analyses cannot define a causal relationship.
Thyroid-disrupting activity has emerged for a broad set of anthropogenic chemicals, with the best evidence being gained for polychlorinated biphenyls, polybrominated diphenyl ethers, dioxins, bisphenols, phthalates, pesticides, and heavy metals.
A series of case-control studies, assessing exposure to thyroid-disrupting agents, as measured on biological matrices, have been recently performed providing the following insights: a) positive relationship with thyroid cancer was found for phthalates, bisphenols, the heavy metals cadmium, copper, and lead; b) polybrominated diphenyl ethers exposure showed no relationship with thyroid cancer c) controversial results were reported for polychlorinated biphenyls and pesticides. However, such studies cannot demonstrate the causal link with disease occurrence, as exposure is assessed after tumour development.
Studies with different methodological approach are therefore required for defining the role of anthropogenic environmental chemicals in thyroid carcinogenesis.
Thyroid effects of endocrine disrupting chemicals
2012, Molecular and Cellular Endocrinology
Citation Excerpt :
In vitro studies showed TPO inhibition by phenol compounds (Schmutzler et al., 2004) as well as interference with binding proteins (Kudo and Yamauchi, 2005; Yamauchi et al., 2003). Methoxychlor was found to decrease hepatic deiodinase activity (Zhou et al., 1995). Thus, pesticides, in particular chlorinated compounds and phenols, show thyroid disrupting properties.
In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert thyroid effects through a variety of mechanisms of action, and some animal experiments and in vitro studies have focused on elucidating the mode of action of specific chemical compounds. Long-term human studies on effects of environmental chemicals on thyroid related outcomes such as growth and development are still lacking. The human exposure scenario with life long exposure to a vast mixture of chemicals in low doses and the large physiological variation in thyroid hormone levels between individuals render human studies very difficult. However, there is now reasonably firm evidence that PCBs have thyroid-disrupting effects, and there is emerging evidence that also phthalates, bisphenol A, brominated flame retardants and perfluorinated chemicals may have thyroid disrupting properties.
Toxicology of DDT and Some Analogues
2010, Hayes' Handbook of Pesticide Toxicology
This chapter describes aspects of the known toxicity of DDT and its analogues such as methoxychlor. DDT came to widespread attention because it dramatically controlled typhus and malaria in wartime. Later it was implicated in the injury of a wide variety of wildlife. This study covers details of storage and excretion of DDT in humans as well as toxic actions in humans and experimental animals. The first perceptible effect of DDT intoxication in animals is abnormal susceptibility to fear, with violent reaction to normally subthreshold stimuli. There is definite motor unrest and increased frequency of spontaneous movements. As poisoning increases, hyperirritability like that seen in strychnine poisoning develops, but convulsions do not appear at this time. Poisoning produced by repeated doses of DDT differs from that produced by a single dose only insofar as the animal may be gradually debilitated, especially by malnutrition. If food intake is maintained, tremor may last for weeks or even, intermittently, for months. If the animals survive a short time after dosing stops, recovery is complete. Its metabolism is a complex affair and predominance of exact sequences is probably tissue- and species-dependent as well as predomination of particular organs in an individual. Although effects on wildlife due to accumulation up the food chain are well recorded, people seem to be remarkably resistant to any toxic effects of DDT even at very high exposure levels. Recent hypotheses about subtle effects on endocrine disruption, including some cancers, following chronic or neonatal exposures to these chemicals at low levels, although important, are still far from substantiated.
Toxicology of DDT and Some Analogues
2010, Hayes' Handbook of Pesticide Toxicology, Third Edition: Volume 1
This chapter describes aspects of the known toxicity of DDT and its analogues such as methoxychlor. DDT came to widespread attention because it dramatically controlled typhus and malaria in wartime. Later it was implicated in the injury of a wide variety of wildlife. This study covers details of storage and excretion of DDT in humans as well as toxic actions in humans and experimental animals. The first perceptible effect of DDT intoxication in animals is abnormal susceptibility to fear, with violent reaction to normally subthreshold stimuli. There is definite motor unrest and increased frequency of spontaneous movements. As poisoning increases, hyperirritability like that seen in strychnine poisoning develops, but convulsions do not appear at this time. Poisoning produced by repeated doses of DDT differs from that produced by a single dose only insofar as the animal may be gradually debilitated, especially by malnutrition. If food intake is maintained, tremor may last for weeks or even, intermittently, for months. If the animals survive a short time after dosing stops, recovery is complete. Its metabolism is a complex affair and predominance of exact sequences is probably tissue- and species-dependent as well as predomination of particular organs in an individual. Although effects on wildlife due to accumulation up the food chain are well recorded, people seem to be remarkably resistant to any toxic effects of DDT even at very high exposure levels. Recent hypotheses about subtle effects on endocrine disruption, including some cancers, following chronic or neonatal exposures to these chemicals at low levels, although important, are still far from substantiated.
Drug and environmental safety: thyroid endocrine disruption
2008, Endocrinologia y Nutricion
La exposición humana a compuestos químicos que interfieren con la homeostasis hormonal es bien conocida, a pesar de que la evidencia sea muy desigual para los distintos sistemas hormonales. Mientras que la disrupción endocrina de los esteroides (estrógenos y andrógenos) ha merecido gran atención, la de la homeostasis de las hormonas tiroideas está mal entendida, si se exceptúa lo que se refiere a la captación de yodo. La lista de disruptores endocrinos que interfieren con la síntesis, la circulación, la unión a receptores específicos, el metabolismo y la degradación de las hormonas tiroideas crece día a día. A los bifenilos policlorados (PCB), las dioxinas y los furanos, se unen ahora los compuestos bromados retardadores de la llama, los bisfenoles y los ftalatos. Cambios sutiles en las concentraciones de las hormonas tiroideas pueden ocasionar efectos adversos en períodos esenciales del desarrollo, de tal manera que se empieza a ver los efectos de tal exposición ahora, una vez que los mecanismos que ligan hormonas tiroideas y neurodesarrollo son cada vez más evidentes.
Human exposure to environmental chemicals that disrupt endocrine homeostasis has been related to several hormone systems. Sex hormones (estrogens and androgens) have received special attention, but thyroid hormone disruption is not so well known except in the special case of iodine intake deficiency. The list of chemicals that alter synthesis, circulation, binding to specific receptors, metabolism and degradation of thyroid hormones increases daily. Brominated flame retardants, bisphenols and phthalates are now included alongside polychlorinated biphenyls (PCBs), dioxins and furans. Subtle changes in circulating thyroid hormones may have undesirable effects during development. As our understanding of the role of thyroid hormones in neurodevelopment improves, exposure to environmental thyroid disruptors becomes a matter of increasing concern.
The role of type I and type II 5′ deiodinases on hexachlorobenzene- induced alteration of the hormonal thyroid status
2005, Toxicology
Treatment of male Wistar rats with hexachlorobenzene (HCB) (1000 mg/kg b.w.) for 3–30 days decreases circulating levels of thyroxine (T₄) but does not affect triiodothyronine (T₃). Time courses were determined for 5′ deiodinase type I (5′ D-I) activity in thyroid, liver, and kidney and 5′ deiodinase type II (5′ D-II) activity in brown adipose tissue (BAT) to test the possibility that increased deiodinase activity might contribute to the maintenance of the serum T₃ level. Specific 5′ D-I activity was increased in the thyroid at 21 days and thereafter. No significant changes were observed in the liver, however, total 5′ D-I activity in this tissue was increased at 30 days of treatment as a consequence of liver weight enhancement. HCB decreased kidney 5′ D-I activity after 15 days, and BAT 5′ D-II activity after 21 days of treatment. Total body 5′ D-I activity was significantly increased by 30 days of HCB-treatment. HCB increased the activity of hepatic T₄ uridine diphosphoglucuronosyl transferase (UDPGT) in a time-dependent manner, without changes in T₃ UDPGT. We propose that increased T₄ to T₃ conversion in the thyroid and in the greatly enlarged liver may account for the maintenance of serum T₃ concentration in hypothyroxinemic HCB-treated rats.

View all citing articles on Scopus

View full text

Regular ArticleCytochrome P450 Catalyzed Covalent Binding of Methoxychlor to Rat Hepatic, Microsomal Iodothyronine 5′-Monodeiodinase, Type I: Does Exposure to Methoxychlor Disrupt Thyroid Hormone Metabolism?

Abstract

Regular Article
Cytochrome P450 Catalyzed Covalent Binding of Methoxychlor to Rat Hepatic, Microsomal Iodothyronine 5′-Monodeiodinase, Type I: Does Exposure to Methoxychlor Disrupt Thyroid Hormone Metabolism?