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Effects of the pesticide methoxychlor on gene expression in the liver and testes of the male largemouth bass (Micropterus salmoides).

ABSTRACT: The organochlorine pesticide methoxychlor (MXC) is an environmental estrogen known to stimulate the expression of the egg-yolk protein, vitellogenin (Vtg) in fish species. To begin to understand the underlying mechanisms for how MXC exerts its deleterious effects on the endocrine system, male largemouth bass (Micropterus salmoides) were treated with 2.5, 10, or 25mg/kg MXC and compared to fish pair-treated with 1mg/kg 17 beta-estradiol (E2), and vehicle control. Fish were sacrificed 24, 48, or 72 h following treatment. The liver and testes were then assayed for changes in expression of the three bass estrogen receptors (ERs alpha, beta a, and beta b) in tissues, as well as Vtg and cytochrome P450 (CYP) 3A isoform 68 in the liver and steroidogenic acute regulatory protein (StAR) in the testes. In the liver, significant increases in gene expression were seen for each of the genes measured by 24 h and each returned to the level of the vehicle by 72 h. Total testosterone 6 beta-hydroxylase activity, reflective of CYP3A activity, was also increased by 24h for all of the exposures. In the testes, ER alpha was unaffected by any treatment, ERbetaa was up-regulated only by MXC, peaking at 24h for the 2.5 and 10mg/kg MXC and at 48 h for the 25mg/kg MXC treatment. By 72 h, the MXC effects had disappeared, while E2 significantly decreased the expression of ER beta a mRNA. ER beta b expression in the testes was stimulated by all concentrations of MXC by 24 h and the effect remained up to 72 h, whereas E2 had no effect. Finally, StAR expression was also found to be decreased by E2 and all MXC treatments. However, the effect on StAR expression by E2 occurred within 24h, while the effect by all concentrations of MXC was not seen until 72 h after treatment. The stimulatory effects of E2 and 25mg/kg MXC on the expression of the ERs in the liver were opposite to the responses seen in the testes, suggesting an inverted relationship between these two tissue types. These results provide a possible mechanism showing that alterations in reproductive signaling in male fish by xenoestrogens not only increase Vtg expression in the liver, but may also decrease reproductive success by muting some of the estrogen signals required for sperm production.

SUBMITTER: Blum JL

PROVIDER: S-EPMC3004021 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Effects of the pesticide methoxychlor on gene expression in the liver and testes of the male largemouth bass (Micropterus salmoides).

Blum Jason L JL Nyagode Beatrice A BA James Margaret O MO Denslow Nancy D ND

Aquatic toxicology (Amsterdam, Netherlands) 20080103 4

The organochlorine pesticide methoxychlor (MXC) is an environmental estrogen known to stimulate the expression of the egg-yolk protein, vitellogenin (Vtg) in fish species. To begin to understand the underlying mechanisms for how MXC exerts its deleterious effects on the endocrine system, male largemouth bass (Micropterus salmoides) were treated with 2.5, 10, or 25mg/kg MXC and compared to fish pair-treated with 1mg/kg 17 beta-estradiol (E2), and vehicle control. Fish were sacrificed 24, 48, or 7 ...[more]

PMID: 18279978

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Project description:Toxaphene is an organochlorine pesticide and environmental contaminant that is concerning due to its atmospheric transport and persistence in soil. In Florida, toxaphene and other organochlorine pesticides were used heavily in agriculture on the north shore of Lake Apopka and they are still detectable in soil. Wild largemouth bass that inhabit the lake and the marshes along the north shore have been exposed to a variety of organochlorine pesticides including dieldrin, methoxychlor, and p,p'-DDE, among others. While these other organochlorine pesticides have been studied for their endocrine disrupting effects in largemouth bass, there is little information for toxaphene. In this study, male and female largemouth bass were given food containing 50 mg/kg toxaphene for almost 3 months, to achieve tissue levels similar to those found in fish at Lake Apopka. Sex-specific toxicity was then evaluated by measuring various reproductive endpoints and transcriptomic changes. In females, gonadosomatic index showed a trend towards reduction (p = 0.051) and plasma vitellogenin was reduced by ~40% relative to controls. However plasma levels of 17β-estradiol and testosterone were not perturbed by toxaphene exposure. These data suggest that toxaphene does not act as a weak estrogen as many other organochlorine pesticides do, but rather appears to be acting as an antiestrogen in female fish. There were no obvious changes in the gonadosomatic index and plasma hormones in male bass. However, ex vivo explant experiments revealed that toxaphene prevented human chorionic gonadotropin-stimulated testosterone production in the testis. This suggested that toxaphene had anti-androgenic effects in males. Subsequent transcriptomic analyses of the testis revealed that androgen receptor/beta-2-microglobulin signaling was up-regulated while insulin-related pathways were suppressed with toxaphene, which could be interpreted as a compensatory response to androgen suppression. In the male liver, the transcriptome analysis revealed an overwhelming suppression in immune-related signaling cascades (e.g. lectin-like receptor and ITSM-Containing Receptor signaling, CD16/CD14 Proinflammatory Monocyte Activation, and CD38/CD3-JUN/FOS/NF-kB Signaling in T-cell Proliferation). Overall, this study showed that toxaphene induced sex-specific effects. The transcriptomic and physiological responses observed can contribute to the development of adverse outcome pathways for toxaphene exposure in fish.

Project description:BackgroundOocyte maturation in fish involves numerous cell signaling cascades that are activated or inhibited during specific stages of oocyte development. The objectives of this study were to characterize molecular pathways and temporal gene expression patterns throughout a complete breeding cycle in wild female largemouth bass to improve understanding of the molecular sequence of events underlying oocyte maturation.MethodsTranscriptomic analysis was performed on eight morphologically diverse stages of the ovary, including primary and secondary stages of oocyte growth, ovulation, and atresia. Ovary histology, plasma vitellogenin, 17β-estradiol, and testosterone were also measured to correlate with gene networks.ResultsGlobal expression patterns revealed dramatic differences across ovarian development, with 552 and 2070 genes being differentially expressed during both ovulation and atresia respectively. Gene set enrichment analysis (GSEA) revealed that early primary stages of oocyte growth involved increases in expression of genes involved in pathways of B-cell and T-cell receptor-mediated signaling cascades and fibronectin regulation. These pathways as well as pathways that included adrenergic receptor signaling, sphingolipid metabolism and natural killer cell activation were down-regulated at ovulation. At atresia, down-regulated pathways included gap junction and actin cytoskeleton regulation, gonadotrope and mast cell activation, and vasopressin receptor signaling and up-regulated pathways included oxidative phosphorylation and reactive oxygen species metabolism. Expression targets for luteinizing hormone signaling were low during vitellogenesis but increased 150% at ovulation. Other networks found to play a significant role in oocyte maturation included those with genes regulated by members of the TGF-beta superfamily (activins, inhibins, bone morphogenic protein 7 and growth differentiation factor 9), neuregulin 1, retinoid X receptor, and nerve growth factor family.ConclusionsThis study offers novel insight into the gene networks underlying vitellogenesis, ovulation and atresia and generates new hypotheses about the cellular pathways regulating oocyte maturation.

Dataset Information

Effects of the pesticide methoxychlor on gene expression in the liver and testes of the male largemouth bass (Micropterus salmoides).

Publications

Effects of the pesticide methoxychlor on gene expression in the liver and testes of the male largemouth bass (Micropterus salmoides).

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