Effect of lindane on mitochondrial side-chain cleavage of cholesterol in mice.
TL;DR: The significant inhibition of cholesterol side-chain cleavage by lindane and resultant decrease in the rate of steroidogenesis in the ovary would account for the observed gonadal hormone deficiency and related reproductive disorders in the lindan-fed mice.
About: This article is published in Toxicology.The article was published on 1990-03-30. It has received 26 citations till now. The article focuses on the topics: Pregnenolone & Steroid biosynthesis.
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TL;DR: Data suggest that several currently used pesticides could influence serum concentrations of reproductive and metabolic hormones, particularly thyroxine, the major secretory product of the thyroid and a principal regulator of metabolism.
Abstract: Many pesticides are used in the agricultural environment, and some may have the potential to disrupt reproductive or endocrine function. Ewes, in separate groups of 6, received orally into their rumen either empty gelatin capsules or capsules containing chlorpyrifos (12.5 mg/kg), trifluralin (17.5 mg/kg), lindane (2.5 mg/kg), or pentachlorophenol (2 mg/kg) 2 times per week for 43 d. Dimethoate (0.2 mg/kg), carbofuran (0.30 mg/kg), 2,4-dichlorophenoxyacetic acid (10 mg/kg), or triallate (5 mg/kg) was given 3 times per week. After 36 d of treatment, blood samples were taken every 12 min for 6 h for hormone analysis. Ewes were euthanized at the end of the study for necropsy and histopathology. No overt signs of toxicity were seen, and body weight was not affected by treatment. Carbofuran caused a significant increase in serum concentrations of thyroxine compared to control ewes, but all other pesticides, except trifluralin, resulted in a marked decrease in thyroxine concentrations. Serum concentrations of cortisol were significantly increased by trifluralin and chlorpyrifos. Concentrations of insulin in serum were markedly increased in ewes given dimethoate, lindane, trifluralin, triallate, and pentachlorophenol, and concentrations of estradiol were also significantly increased in ewes given lindane and trifluralin. Mean serum concentrations of LH were markedly decreased by trifluralin, and basal LH concentrations were significantly decreased by lindane, dimethoate, and trifluralin but increased by triallate. Both pentachlorophenol and triallate caused a significant increase in severity of oviductal intraepithelial cysts in ewes. Data suggest that several currently used pesticides could influence serum concentrations of reproductive and metabolic hormones, particularly thyroxine, the major secretory product of the thyroid and a principal regulator of metabolism.
195 citations
TL;DR: Many endocrine disruptors act as antiandrogens via directly inhibiting one or more enzymes for testosterone biosynthesis and metabolic activation, including industrial materials and pesticides/biocides and plant constituents.
Abstract: The Leydig cells of the testis have the capacity to biosynthesize testosterone from cholesterol. Testosterone and its metabolically activated product dihydrotestosterone are critical for the development of male reproductive system and spermatogenesis. At least four steroidogenic enzymes are involved in testosterone biosynthesis: Cholesterol side chain cleavage enzyme (CYP11A1) for the conversion of cholesterol into pregnenolone within the mitochondria, 3β-hydroxysteroid dehydrogenase (HSD3B), for the conversion of pregnenolone into progesterone, 17α-hydroxylase/17,20-lyase (CYP17A1) for the conversion of progesterone into androstenedione and 17β-hydroxysteroid dehydrogenase (HSD17B3) for the formation of testosterone from androstenedione. Testosterone is also metabolically activated into more potent androgen dihydrotestosterone by two isoforms 5α-reductase 1 (SRD5A1) and 2 (SRD5A2) in Leydig cells and peripheral tissues. Many endocrine disruptors act as antiandrogens via directly inhibiting one or more enzymes for testosterone biosynthesis and metabolic activation. These chemicals include industrial materials (perfluoroalkyl compounds, phthalates, bisphenol A and benzophenone) and pesticides/biocides (methoxychlor, organotins, 1,2-dibromo-3-chloropropane and prochloraz) and plant constituents (genistein and gossypol). This paper reviews these endocrine disruptors targeting steroidogenic enzymes.
134 citations
Additional excerpts
...Indeed, lindane inhibits mouse CYP11A1 activity [106]....
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TL;DR: Results are consistent with the hypothesis that α-, δ-, and γ-HCH inhibited steroidogenesis by reducing StAR protein expression, an action that may contribute to the pathogenesis of lindane-induced reproductive dysfunction.
Abstract: Lindane, the γ isomer of hexachlorocyclohexane (HCH), is one of the oldest synthetic pesticides still in use worldwide. Numerous reports have shown that this pesticide adversely affects reproductive function in animals. Although the pathogenesis of reproductive dysfunction is not yet fully understood, recent reports indicate that lindane can directly inhibit adrenal and gonadal steroidogenesis. Because Leydig cells play a pivotal role in male reproductive function through the production of testosterone, the mouse MA-10 Leydig tumor cell line was used to assess the potential effects of γ-HCH and its isomers, α-HCH and δ-HCH, on steroid production, steroidogenic enzyme expression and activity, and steroidogenic acute regulatory (StAR) protein expression. StAR mediates the rate-limiting and acutely regulated step in hormone-stimulated steroidogenesis, the intramitochondrial transfer of cholesterol to the P450scc enzyme. Our studies demonstrate that α-, δ-, and γ-HCH inhibited dibutyryl ([Bu]2) cAMP-...
127 citations
Cites background or result from "Effect of lindane on mitochondrial ..."
...Previously, investigators demonstrated that lindane did not reduce P450scc activity in Y-1 adrenal cells following acute exposure [12], but did reduce 3b-HSD activity in isolated granulosa and Leydig cells following chronic exposure in vivo [2, 6]....
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...Finally, providing direct evidence that lindane inhibits steroid production, lindane and its isomers, a-HCH and d-HCH block the conversion of cholesterol to pregnenolone in steroidogenic cells in vitro without affecting P450scc activity [2, 6, 12]....
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...The observation that these isomers inhibited steroid production in MA-10 cells by limiting substrate availability is identical to the situation seen in Y-1 adrenal tumor and isolated Leydig and granulosa cells [2, 6, 12]....
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TL;DR: The H295R cell line provides a good in vitro system for the analysis of the human adrenal steroidogenic pathway at the level of hormone production and gene expression and can be used for the rapid detection of adrenal endocrine disruption and as a tool for mechanistic studies.
Abstract: The focus on the refinement, reduction and replacement of animal use in toxicity testing requires the development of cell-based systems that mimic the effects of xenobiotics in human tissues. The human adrenocortical carcinoma cell line, H295R, has been proposed as a model for studies on adrenal steroidogenesis and its disruption. In this study, expression profiles for nine adrenal steroidogenic genes were characterized in H295R cells using real-time RT-PCR. Treatment with forskolin increased cortisol secretion and stimulated transcription of all the steroidogenic genes except SULT2A1. The transcript profile from H295R cells in the presence and absence of forskolin was compared with the transcript profile from human adrenal glands. The gene expression pattern observed in the forskolin-treated H295R cells was more similar to that in the human adrenal gland, than the expression pattern in untreated cells. To examine H295R cells as a possible in vitro system for the assessment of adrenal disruption using molecular endpoints, the insecticide lindane (gamma-hexachlorocyclohexane) was used. In vivo, lindane has been shown to inhibit testicular, ovarian and adrenal steroidogenesis. It was demonstrated that lindane reduced cortisol secretion, downregulated the expression of a subset of the genes encoding steroidogenic enzymes and repressed transcriptional activation of the steroidogenic acute regulatory protein (StAR) gene promoter. Thus the H295R cell line provides a good in vitro system for the analysis of the human adrenal steroidogenic pathway at the level of hormone production and gene expression. This in vitro test can be used for the rapid detection of adrenal endocrine disruption and as a tool for mechanistic studies.
72 citations
TL;DR: The pesticides affected reproduction only after estrous synchronization, whereas PCP consistently disrupted thyroid function, most likely through a direct effect on the thyroid gland.
Abstract: There is concern over the potential endocrine-modulating effects of long-term exposure to pesticides. In this study, ewe lambs were exposed to lindane and pentachlorophenol (PCP) from conception to necropsy at 67 wk. of age. The ewe lambs (and their mothers) were given untreated feed (n = 6) or feed treated with 1 mg/kg body weight/day of lindane (n = 8) or PCP (n = 13). Estrus was synchronized at 32 wk. of age, and ewe lambs were exposed to vasectomized rams. Ewe lambs were then exposed to intact rams during the following two natural estrous periods and subsequent reproductive performance was monitored. Serum was collected every 2 wk. during development, daily during the synchronized cycle and frequently (every 15-60 min) for 6-18 h either with or without stimulation with thyroid-stimulating hormone (TSH) during the synchronized luteal phase or TSH/thyroid-releasing hormone (TRH) at 65-66 wk of age. Ewe lambs fed a PCP-treated diet had a significantly reduced serum concentration of both T4 and free T4, and a reduction in the magnitude and duration of the T4 and free T4 response to TSH, despite normal endogenous levels of TSH and a normal TSH response to TRH. PCP exposure had a less detrimental influence on unstimulated T3 levels; however, the T3 (but not reverse T3) response to TSH was markedly reduced in PCP-treated ewe lambs. Ewe lambs given lindane also had a significantly reduced serum concentration of T4; however, despite continued exposure to lindane, T4 levels returned to normal by 10 wk. of age. Detrimental effects on reproductive function were only seen following estrous synchronization when both PCP and lindane exposure reduced the number of corpora lutea (CL) and total CL volume and increased luteinizing hormone (LH) pulse frequency. In addition, lindane-treated ewes had shorter estrous cycles and lower luteal progesterone concentrations. No marked effects of pesticides were seen on fertility following mating during natural estrous periods. In conclusion, the pesticides affected reproduction only after estrous synchronization, whereas PCP consistently disrupted thyroid function, most likely through a direct effect on the thyroid gland.
53 citations
References
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TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.
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280 citations
TL;DR: In reviewing the regulation of steroidogenesis, the chapter points out two major factors—the properties of individual enzymes and their arrangement in lipid membranes; these are important in the microsomal process.
Abstract: Publisher Summary This chapter provides an overview of cellular organization for steroidogenesis. There are two approaches: purification and reconstitution, which resemble the classical steps of organic chemistry—namely, isolation, and synthesis. It is clear that the methods of cell biology must be applied to steroidogenesis—that is, it is necessary to understand how the steroidogenic cell is organized in such a way as to permit the steps of steroidogenesis to proceed in an orderly fashion, so that a regulated output of the completed hormones can be achieved. In reviewing the regulation of steroidogenesis, the chapter points out two major factors—the properties of individual enzymes and their arrangement in lipid membranes; these are important in the microsomal process. The major steroidogenic organs are the adrenal cortex, testis, ovary, and placenta. Although each organ produces its own characteristic profile of steroid hormones, the enzymes involved and the organization of the process are fundamentally similar in every case. Differences in the hormones produced by the organs result from the differences in the amounts of the various steroidogenic enzymes. The chapter also discusses the organization of the steroidogenic cell.
122 citations
TL;DR: For more than 15 years it has been known that the abundant adrenal secretory product, dehydroisoandrosterone sulfate, can be biosynthesized from cholesterol sulfate through pathways that involve sulfated intermediates.
Abstract: Introduction The generally accepted pathways of steroidogenesis are customarily presented by a scheme such as that shown in Fig. 1. This two-dimensional picture can be conveniently reproduced on a printed page and is easily memorized. It provides, however, too simplistic a view which can lead to serious misconceptions. By depicting the biochemical transformations it concentrates on the apparent common features of the various pathways but ignores many important differences. The scheme indicates that one sterol, cholesterol, serves as a precursor for all the hormones. The possibility that other derivatives of cholesterol may also be progenitors of important steroidal products is not taken into account. Cholesterol esters, particularly cholesterol sulfate, are examples of such precursors. For more than 15 years (1) it has been known that the abundant adrenal secretory product, dehydroisoandrosterone sulfate, can be biosynthesized from cholesterol sulfate through pathways that involve sulfated intermediates w...
115 citations