The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on fetal male rat steroidogenesis
Department of Physiology, University of Turku, Turku, Finland. International Journal of Andrology
(Impact Factor: 3.7).
10/2009; 32(5):575-85. DOI: 10.1111/j.1365-2605.2008.00900.x
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic and widely investigated dioxin congener. In utero and lactational exposure to TCDD results in developmental and reproductive defects that are the most sensitive endpoints for TCDD toxicity. TCDD has a potential to interfere with steroid metabolism, but the mechanisms by which this occurs are not well understood. In this study, we investigated the effects of TCDD on prenatal rat steroidogenesis. Pregnant Sprague-Dawley female rats were treated once with TCDD (0, 0.3 or 1 microg/kg) by gavage on embryonic day (ED) 11 and the expression levels of androgen (AR) and estrogen receptors (ER), steroidogenic enzymes (P450scc and 3beta-HSD) and four regulatory factors (StAR, SF-1, GATA-4 and Insl-3) involved in foetal Leydig cell and adrenal function were analysed on ED 19.5. Hormonal status of male foetuses was determined by measuring testicular testosterone (T) levels, plasma luteinizing hormone (LH) and corticosterone concentrations. In utero exposure to TCDD reduced intratesticular T of foetal males (significant at 0.3 microg/kg TCDD) and tended to reduce the protein expression of ERalpha and AR of foetal male rat testis. Foetal male rat plasma LH levels were significantly reduced at the dose of 1 microg/kg TCDD, while corticosterone levels tended to be increased possibly because of the TCDD-induced stress. Only minor alterations in steroidogenesis were observed in rat adrenal. mRNA expression of developmental regulatory factors was not influenced by foetal TCDD exposure, except for significantly reduced adrenal SF-1. The results demonstrate that maternal exposure to TCDD suppressed testicular steroidogenesis of 19.5-day-old foetal male Sprague-Dawley rat. The highest dose of TCDD (1 microg/kg) had also an effect on pituitary LH secretion. Our data implicate that TCDD has direct testicular and pituitary effects on foetal male rat but with different dose-responses. These changes can lead to impaired steroidogenesis and it may result in the maldevelopment of the testis and weaken masculinization.
Available from: Rasha M. Khafagy
- "Induction of oxidative stress upon exposure to TCDD is considered to be an important mechanism for the toxic effects of TCDD in mitochondrial fraction and epididymis of rat testis (Latchoumycandane et al., 2002, 2003). Further, it has been reported that TCDD, an endocrine disruptor, causes testicular toxicity in rat by increasing the production of ROS (Dhanabalan and Mathur, 2009; Adamsson et al., 2009). "
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ABSTRACT: TCDD, as an endocrine disruptor, is known to impair testicular functions and fertility. To elucidate the mechanism(s) underlying the testicular effects of TCDD, the potential toxicity of TCDD on Sertoli cells was investigated. Furthermore, the study aims to delineate whether mitochondrial fractions of Sertoli cells are involved in mediating the testicular effects of TCDD. Adult rat Sertoli cells were incubated with (5, 10 or 15nM) of TCDD for 6, 12 or 24h. Cell viability, lactate and LDH leakage into media along with lipid peroxidation, ROS generation, SOD, CAT, GPx, GR, γ-GT and β-glucuronidase activities, GSH content and Δψ(m) were measured. Superoxide anion production, COX and cardiolipin content were measured in mitochondrial fractions. Cell viability was significantly decreased while lactate and LDH leakage into media were increased. ROS generation along with lipid peroxidation was also increased. SOD, CAT, GPx, GR activities and GSH content were significantly decreased. γ-GT and β-glucuronidase activities were also decreased. Superoxide anion production was increased while COX activity and cardiolipin content were decreased in mitochondrial fractions. Moreover, the Δψ(m) was significantly decreased as measured in Sertoli cells. In conclusion, TCDD impairs Sertoli cell functions and this effect is, at least in part, attributed to oxidative stress. We have also found that TCDD increases mitochondrial superoxide anion production and decreases Δψ(m), COX activity and mitochondrial cardiolipin content. Our findings suggest that mitochondria may play an important role in ROS production, leading to the TCDD-induced oxidative stress response and resulting toxicological consequences in rat Sertoli cells.
Available from: ir.ihb.ac.cn
- "observed in H295R cells (Letcher et al., 2005). Minor alterations in adrenal steroidogenesis and significant suppressed testicular steroidogenesis in rats caused by TCDD feeding at a dose of 1 μg/kg were observed (Adamsson et al., 2008). As seen in our studies, significant suppression of the anterior pituitary POMC and adverse effects on early zebrafish interrenal development were observed in simazine and PCB126 treatment groups but not in BADGE and TCDD treatment groups (Figs. "
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ABSTRACT: Adrenocorticotropin (ACTH) has been considered a classic adrenocorticotropic hormone and the key pituitary-derived peptide controlling steroidogenesis in the adult adrenal. ACTH is encoded by the propiomelanocortin (POMC) gene, and its active form is mainly synthesized and processed from the POMC-encoded multihormone precursor in the anterior pituitary. The ACTH level has always been precisely controlled in the signaling cascade of the hypothalamo-pituitary-adrenal (HPA) axis due to its central role. The purpose of this study was to investigate whether the transgenic zebrafish line with EGFP driven by the POMC promoter can be used as a surrogate marker to detect the interference effects on anterior pituitary POMC expression caused by chemicals in teleost. The Tg (POMC:EGFP) fish treated for 4days with the known adrenergic agents, dexamethasone (Dex) or aminoglutethimide (AG), exhibited altered levels of EGFP and POMC expression in the anterior domain of pituitary corticotrophs. Whole-mount in situ hybridization revealed impaired patterns of expression of the zebrafish ftz-fl gene (ff1b), a key molecular marker for early interrenal development. Next, several chemicals and six commonly used organophosphorus compounds (OPs) were tested for their effects on anterior pituitary POMC expression and early interrenal development. Our preliminary screening analyses indicated that simazine and 3,3',4,4'5-pentachlorobiphenyl (PCB126) could interfere with anterior pituitary POMC expression and interrenal development in fish. In summary, our results demonstrated that the Tg (POMC:EGFP) zebrafish line might be employed as a specific and reproductive in vivo assessment model for the effects of endocrine disruption on HPA signaling.
Available from: Konstantin Svechnikov
- "The effects of TCDD on prenatal testis functioning is a dose-dependent process. It has been recently demonstrated that prenatal treatment of pregnant rats with low (0.3 μg/kg) dose of TCDD significantly reduced intratesticular testosterone of fetal males, while high (1 μg/kg) dose attenuated LH production by the pituitary of exposed male fetuses . One possible explanation for TCDD-induced decrease in testicular steroidogenesis could be the reduction in Leydig cell number. "
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ABSTRACT: During the past decades, a large body of information concerning the effects of endocrine disrupting compounds (EDCs) on animals and humans has been accumulated. EDCs are of synthetic or natural origin and certain groups are known to disrupt the action of androgens and to impair the development of the male reproductive tract and external genitalia. The present overview describes the effects of the different classes of EDCs, such as pesticides, phthalates, dioxins, and phytoestrogens, including newly synthesized resveratrol analogs on steroidogenesis in Leydig cells. The potential impact of these compounds on androgen production by Leydig cells during fetal development and in the adult age is discussed. In addition, the possible role of EDCs in connection with the increasing frequency of abnormalities in reproductive development in animals and humans is discussed.
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