Stimulation of the pituitary–adrenal axis and of adrenocortical steroidogenesis ex vivo by administration of di-2-ethylhexyl phthalate to prepubertal male rats

Supornsilchai, Vichit; Söder, Olle; Svechnikov, Konstantin

doi:10.1677/joe-06-0004

Cited by 29 publications

(16 citation statements)

References 34 publications

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“…The dose of DEHP (500 mg/kg) used in this investigation was shown to effectively increase the levels of corticosterone and ACTH in plasma of 20-and 40-day-old male rats (Supornsilchai et al 2007). As in our study, no overt toxicity was observed in these animals.…”

Section: Discussionsupporting

confidence: 74%

“…The existence of such an indirect action is supported by the observation that exposure of pre-pubertal male rats to DEHP for 28 days stimulated their pituitary-gonadal axis, thereby resulting in elevated serum levels of LH (Akingbemi et al 2001), as well as by the findings that chronic administration of DEHP to male rats results in hypertrophy of gonadotropes in the anterior pituitary and promotes development of pituitary tumors (Kluwe et al 1982). Recently, we have also shown that oral exposure of 20-and 40-day-old male rats to DEHP elevates their serum level of ACTH (Supornsilchai et al 2007).…”

Section: Discussionmentioning

confidence: 70%

“…This dose of DEHP has been shown to effectively elicit response, but not toxicity in male rats of approximately the same age (Supornsilchai et al 2007). Twenty-four hours after the last gavage, the animals were anesthetized with pentobarbital, blood samples collected by intracardiac puncture, and plasma prepared by centrifugation at 2500 g for 15 min, and thereafter maintained at K80 8C for subsequent analysis of progesterone, estradiol, and LH.…”

Section: Animalsmentioning

confidence: 96%

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The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats

Svechnikova

Svechnikov

Söder

2007

Journal of Endocrinology

120

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Phthalate esters are known to exert harmful effects on mammalian reproduction and fertility, but their potential adverse effects on the hormonal functions of the ovary have not yet been elucidated in detail. Here, we investigated the effects of di-(2-ethylhexyl) phthalate (DEHP) on the hypothalamic-pituitary-gonadal axis of young developing female rats, as well as on ex vivo steroidogenesis by granulosa cells (GCs) and secretion of LH by gonadotropes. Exposure of 20-day-old female rats to 500 mg DEHP by oral gavage once daily for 10 days reduced their serum levels of progesterone and estradiol, while tending to enhance levels of LH. Furthermore, primary cultures of GCs isolated from these rats exhibited an attenuated capacity to produce progesterone in response to stimulation by LH and FSH, as well as a lower degree of transport of endogenous cholesterol into mitochondria. Moreover, the ability of primary cultures of pituitary cells isolated from DEHPtreated rats to produce and secrete LH in response to GnRH was significantly enhanced. In addition, 2-ethylhexanoic acid, a metabolite of DEHP, significantly potentiated GnRH-stimulated production of LH by cultures of pituitary cells isolated from untreated 20-day-old female rats. Together, these data indicate that DEHP exerts dual effects on the pituitary-gonadal axis, stimulating the hormonal function of the pituitary and, at the same time, by inhibiting steroidogenesis by GCs.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 70%

Section: Animalsmentioning

confidence: 96%

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The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats

Svechnikova

Svechnikov

Söder

2007

Journal of Endocrinology

120

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“…DEHP was demonstrated to suppress tamoxifen-induced apoptosis possibly linked to its estrogenic effects in pituitary GH 3 cells (Yamasaki et al 2004;Kim et al 2007). This compound was noted to exert an agedependent influence on the pituitary-adrenocortical axis in vivo (Supornsilchai et al 2007). An interesting report by Li et al (2011) showed that the concentrations of phthalate esters, including DEHP, in semen or serum samples were positively associated with circulating prolactin levels in adult men.…”

Section: Introductionmentioning

confidence: 99%

The inhibition by di(2-ethylhexyl)-phthalate of erg-mediated K+ current in pituitary tumor (GH3) cells

Yang

Yeh

et al. 2012

Arch Toxicol

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DEHP (bis(2-ethylhexyl)-phthalate) known to be an endocrine-disrupting chemical is a widely used phthalate. Little information regarding the effects of phthalate esters on ion currents is available. In this study, the effects of DEHP and other phthalate esters (DBEP: di(2-butoxyethyl)-phthalate and DMGP: di(2-methylglycol)-phthalate) on ion currents were investigated in pituitary GH₃ cells. Hyperpolarization-elicited K⁺ currents in GH3 cells bathed in high-K⁺, Ca²⁺-free solution were examined to evaluate the effects of DEHP, DBEP, and DMGP on the ether-a`-go-go-related-gene (erg) K⁺ current (IK(erg)). Addition of DEHP to GH₃ cells suppressed the amplitude of IK(erg) in a concentration-dependent manner with an IC₅₀ value of 16.3 μM. With a two-pulse protocol, addition of DEHP shifted the activation curve of IK(erg) to a depolarized potential by approximately 10 mV with no change in the rate of IK(erg) deactivation. This compound did not have any effects on delayed rectifier K⁺ current in GH₃ cells, while 4-aminopyridine-3-methanol (100 μM) suppressed this current significantly. DBEP (30 μM) had little or no effect on IK(erg), while DMGP (30 μM) slightly reduced it. In inside-out configuration, DEHP (30 μM) applied to the bath slightly reduced the activity of large-conductance Ca²⁺-activated K⁺ channels. DEHP (30 μM) increased the frequency of spontaneous action potentials (APs); however, this compound at the same concentration had no effect on AP firing in KCNH2 siRNA-transfected GH₃ cells. The effects described herein can contribute to their actions on functional activity of endocrine or neuroendocrine cells if similar results are found in vivo.

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“…Oral exposure to DEHP (500 mg/kg bw/day for 4 days) increased concentrations of ACTH and corticosterone in treated male rats at 20 and 40 days of age; whereas no effects were observed in adult (60 days of age) males (Supornsilchai et al, 2007). Isolated adrenocortical cells from the 20 and 40 day old treated rats were more sensitized to the effects of ACTH, dibutyrl cAMP, and 22R-hydroxylase, as evidenced by increased production of corticosterone and ACTH treatment stimulated greater transport of endogenous cholesterol into the mitochondria.…”

Section: Mechanisms By Which Endocrine Disruptors May Affect Parentalmentioning

confidence: 98%

Bisphenol A and phthalate endocrine disruption of parental and social behaviors

Rosenfeld

2015

Front. Neurosci.

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Perinatal exposure to endocrine disrupting chemicals (EDCs) can induce promiscuous neurobehavioral disturbances. Bisphenol A and phthalates are two widely prevalent and persistent EDCs reported to lead to such effects. Parental and social behaviors are especially vulnerable to endocrine disruption, as these traits are programmed by the organizational-activational effects of testosterone and estrogen. Exposure to BPA and other EDCs disrupts normal maternal care provided by rodents and non-human primates, such as nursing, time she spends hunched over and in the nest, and grooming her pups. Paternal care may also be affected by BPA. No long-term study has linked perinatal exposure to BPA or other EDC and later parental behavioral deficits in humans. The fact that the same brain regions and neural hormone substrates govern parental behaviors in animal models and humans suggests that this suite of behaviors may also be vulnerable in the latter. Social behaviors, such as communication, mate choice, pair bonding, social inquisitiveness and recognition, play behavior, social grooming, copulation, and aggression, are compromised in animal models exposed to BPA, phthalates, and other EDCs. Early contact to these chemicals is also correlated with maladaptive social behaviors in children. These behavioral disturbances may originate by altering the fetal or adult gonadal production of testosterone or estrogen, expression of ESR1, ESR2, and AR in the brain regions governing these behaviors, neuropeptide/protein hormone (oxytocin, vasopressin, and prolactin) and their cognate neural receptors, and/or through epimutations. Robust evidence exists for all of these EDC-induced changes. Concern also exists for transgenerational persistence of such neurobehavioral disruptions. In sum, evidence for social and parental deficits induced by BPA, phthalates, and related chemicals is strongly mounting, and such effects may ultimately compromise the overall social fitness of populations to come.

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Stimulation of the pituitary–adrenal axis and of adrenocortical steroidogenesis ex vivo by administration of di-2-ethylhexyl phthalate to prepubertal male rats

Cited by 29 publications

References 34 publications

The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats

The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats

The inhibition by di(2-ethylhexyl)-phthalate of erg-mediated K+ current in pituitary tumor (GH3) cells

Bisphenol A and phthalate endocrine disruption of parental and social behaviors

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