Inhibition of Testicular Steroidogenesis by the Xenoestrogen Bisphenol A Is Associated with Reduced Pituitary Luteinizing Hormone Secretion and Decreased Steroidogenic Enzyme Gene Expression in Rat Leydig Cells

Akingbemi, Benson T.; Sottas, Chantal M.; Koulova, Anna; Klinefelter, Gary R.; Hardy, Matthew P.

doi:10.1210/en.2003-1174

Cited by 452 publications

(319 citation statements)

References 67 publications

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“…There is now growing evidence showing endocrine-disrupting effects of BPA at doses lower than the reference limits (11,12,31,32). The present dose-response study on intestinal permeability shows a half-maximal inhibitory dose for BPA 10 fold below the TDI.…”

Section: Discussionmentioning

confidence: 48%

“…However, recent studies revealed that chronic exposure to these reference doses alters some biological endpoints (8,9), warranting a request for reevaluation of human safe daily intake limits (4,10). To date, most studies examining the estrogenic impact of BPA have focused on reproductive function (11)(12)(13) and, more recently, on brain development (14,15). In contrast, although the gut is in direct contact with orally absorbed BPA, the endocrine impact on the intestinal barrier function remains an unexplored endpoint.…”

mentioning

confidence: 99%

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Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats

Braniste¹,

Jouault²,

Gaultier³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

164

111

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Bisphenol A (BPA), a chemical estrogen widely used in the foodpackaging industry and baby bottles, is recovered in human fluids (0.1-10 nM). Recent studies have reported that BPA is hormonally active at low doses, emphasizing the debate of a risk for human health. Estrogen receptors are expressed in the colon, and although the major route of BPA exposure is food, the effects on gut have received no attention. We first examined the endocrine disrupting potency of BPA on colonic paracellular permeability (CPP), experimental colitis, and visceral sensitivity in ovariectomized rats orally exposed to 5 mg/kg/d BPA (i.e., the no observed adverse effect level), 50 μg/kg/d BPA (i.e., tolerable daily intake), or lower doses. BPA dosedependently decreased basal CPP, with a half-maximal inhibitory dose of 5.2 μg/kg/d, 10-fold below the tolerable daily intake. This correlated with an increase in epithelial tight junction sealing, also observed in Caco-2 cells exposed to 10 nM BPA. When ovariectomized rats were fed with BPA at the no observed adverse effect level, the severity of colitis was reduced, whereas the same dose increased pain sensitivity to colorectal stimuli. We then examined the impact of perinatal exposure to BPA on intestinal permeability and inflammatory response in the offspring. In female rats, but not in male rats, perinatal BPA evoked a decrease of CPP in adulthood, whereas the proinflammatory response of colonic mucosa was strengthened. This study first demonstrates that the xenoestrogen BPA at reference doses influences intestinal barrier function and gut nociception. Moreover, perinatal exposure promotes the development of severe inflammation in adult female offspring only.endocrine disruptor | gut permeability | inflammation | pain | estrogen

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Section: Discussionmentioning

confidence: 48%

mentioning

confidence: 99%

Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats

Braniste¹,

Jouault²,

Gaultier³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

164

111

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“…Presence of BPA in the human endometrium [26] supports the idea that there may be possible interactions between BPA and endogenous estrogen in the local environment. Complex role of BPA in testicular steroidogenesis is also reported recently [27].…”

Section: Discussionmentioning

confidence: 76%

Differences in Serum Bisphenol A Concentrations in Premenopausal Normal Women and Women with Endometrial Hyperplasia

et al. 2004

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Abstract. Exposure to endocrine disrupting chemicals (EDCs) has been raised in relation to its potential for adverse health outcomes. Bisphenol A (BPA) is an estrogenic EDC widely found in plastic products. We determined BPA concentrations in premenopausal women by an enzyme-linked immunosorbent assay and evaluated possible linkage between its contamination levels and endometrial hyperplasia, an estrogen-related disorder of the uterus. It has been implied that higher levels of BPA, which binds to estrogen receptor and plays estrogenic roles may, enhance endometrial hyperplasia. Serum BPA was detectable in all subjects and its concentrations in healthy controls with normal endometrium were 2.5 ± 1.5 ng/ml (mean ± SD). BPA levels in patients with simple endometrial hyperplasia with benign nature were 2.9 ± 2.0 ng/ml and were not significantly different from the controls. Unexpectedly, BPA levels in patients with complex endometrial hyperplasia with malignant potential were 1.4 ± 0.4 ng/ml and significantly lower compared to both control and simple endometrial hyperplasia groups. In addition, we measured the serum BPA levels in postmenopausal endometrial cancer patient (1.4 ± 0.5 ng/ml), which were also significantly lower than control and simple endometrial hyperplasia groups. These findings suggest the presence of associations between BPA exposure and complex endometrial hyperplasia and endometrial cancer. The mode of action of BPA may be more complex than expected and the contradictory results may serve as a clue to addressing the mechanisms of linkage between occurrence of estrogendependent diseases and endocrine disruption.

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“…The details of the primers used, number of cycles, and size of the PCRamplified products are listed in Table 1. The primers used for RT-PCR for StAR protein and cytochrome P 450 scc were gene-specific primers selected according to Akingbemi et al (2004). The 3b-HSD type I and 17b-HSD type III were selected according to Sakaue et al (2002).Ten microliters of each PCR product were analyzed by gel electrophoresis on a 2% agarose gel.…”

Section: Rt-pcrmentioning

confidence: 99%

Effects of polychlorinated biphenyl (Aroclor 1254) on steroidogenesis and antioxidant system in cultured adult rat Leydig cells

Palaniappan¹,

Balaganesh²,

Balasubramanian³

et al. 2007

Journal of Endocrinology

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Polychlorinated biphenyls (PCBs) are ubiquitous and persistent environmental contaminants that disturb normal endocrine functions, including gonadal functions in humans and mammals. In the present study, we examined the direct effects of PCB on rat Leydig cells in vitro. Adult Leydig cells were purified by Percoll gradient centrifugation method and the purity of Leydig cells was also determined by 3b-hydroxysteroid dehydrogenase (3b-HSD) staining method. Purified Leydig cells were exposed to different concentrations (10 K10-10 K7 M) of PCB (Aroclor 1254) for 24 h under basal and LH-stimulated conditions. After the experimental period, cultured media were collected and used for the assay of testosterone and estradiol. The treated cells were used for the quantification of cell-surface LH receptors and activities of steroidogenic enzymes, such as cytochrome P 450 side-chain cleavage enzyme (P 450 scc), 3b-HSD, and 17b-hydroxysteroid dehydrogenase (17b-HSD). Leydig cellular enzymatic antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, g-glutamyl transpeptidase, glutathione-S-transferase, and nonenzymatic antioxidants, such as vitamins C and E, were assayed. Lipid peroxidation (LPO) and reactive oxygen species (ROS) were also estimated in Leydig cells. In addition, total RNA was isolated from control and Aroclor 1254-exposed Leydig cells to monitor the steady-state mRNA levels by reverse transcription(RT)-PCR for steroidogenic acuteregulatory (StAR) protein, cytochrome P 450 scc, 3b-HSD, and 17b-HSD. Our results indicated that Aroclor 1254 (10 K9 , 10 K8 , and 10 K7 M) treatments significantly inhibit basal and LH-stimulated testosterone and estradiol production. In addition, the activities of steroidogenic enzymes, enzymatic and nonenzymatic antioxidants were significantly diminished in a dose-dependent manner. However, LPO and ROS were elevated in a dose-dependent manner under basal and LH-stimulated conditions. RT-PCR analysis of StAR mRNA level showed a decrease only in 10 K7 M dose of Aroclor 1254 treatment, while cytochrome P 450 scc, 3b-HSD, and 17b-HSD mRNAs were drastically decreased in both 10 K8 and 10 K7 M Aroclor 1254 treatment. These findings suggest that PCBs can act directly on Leydig cells to diminish testosterone production by inhibiting gene expression of steroidogenic enzymes and antioxidant system.

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Inhibition of Testicular Steroidogenesis by the Xenoestrogen Bisphenol A Is Associated with Reduced Pituitary Luteinizing Hormone Secretion and Decreased Steroidogenic Enzyme Gene Expression in Rat Leydig Cells

Cited by 452 publications

References 67 publications

Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats

Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats

Differences in Serum Bisphenol A Concentrations in Premenopausal Normal Women and Women with Endometrial Hyperplasia

Effects of polychlorinated biphenyl (Aroclor 1254) on steroidogenesis and antioxidant system in cultured adult rat Leydig cells

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