Disruption of Neuroendocrine Control of Luteinizing Hormone Secretion by Aroclor 1254 Involves Inhibition of Hypothalamic Tryptophan Hydroxylase Activity1

Abstract

Mechanisms governing the effect of polychlorinated biphenyl (PCB) toxicity on hypothalamic serotonergic function and the neuroendocrine system controlling LH secretion were investigated in Atlantic croaker (Micropogonias unulatus) exposed to the PCB mixture Aroclor 1254 (1 microg x g body weight(-1) x day(-1)) in the diet for 30 days. PCB treatment caused a decrease in hypothalamic 5-hydroxytryptamine (5-HT) concentrations and significant inhibition of hypothalamic tryptophan hydroxylase (TPH), the rate-limiting enzyme in 5-HT synthesis, but did not alter the activity of monoamine oxidase, the catabolic enzyme. Further, PCB treatment caused significant decreases in GnRH content in the preoptic-anterior hypothalamic area. Significant decreases in pituitary GnRH receptor concentrations and the LH response to the GnRH analogue (GnRHa) were also observed in PCB-exposed fish, possibly as a consequence of a decline in GnRH release. The possible association between impaired serotonergic and neuroendocrine functions after PCB treatment was explored using serotonergic drugs. Treatment of croaker with p-chlorophenylalanine, an irreversible TPH inhibitor, mimicked the effects of PCB on the GnRH system and the LH response to GnRHa. Bypassing the TPH-dependent hydroxylation step with the administration of 5-hydroxytryptophan restored 5-HT to control levels and prevented the deleterious effects of PCB on the neuroendocrine parameters. Moreover, slow-release GnRH implants prevented the PCB-induced decline in GnRH receptors and restored the LH response to GnRHa, suggesting that GnRH therapy can reverse PCB-induced disruption of LH secretion. These results demonstrate that TPH is one of the targets of PCB neurotoxicity and indicate that a decrease in 5-HT availability in PCB-exposed croaker results in disruption of the stimulatory 5-HT/GnRH pathway controlling LH secretion.

Non-coplanar polychlorinated biphenyl (PCB)-induced immunotoxicity is coincident with alterations in the serotonergic system

“…However, PCBinduced alterations in the serotonergic system have been correlated with neuroendocrine disruption (Khan and Thomas, 1997, 2001, 2004a. In these studies, Khan and Thomas (2001) demonstrated that PCB, acting via inhibition of TPH, reduced hypothalamic 5-HT concentrations resulting in an impairment of gonadotrophin-releasing hormone and leutinizing hormone secretion in Atlantic croaker. A reduction in hormone secretion was also seen in croaker treated with a 5-HT depleting agent (i.e., p-chlorophenylalanine); effects were abrogated following treatment of fish with 5-HTP.…”

Physiological Endpoints for Potential SSRI Interactions in Fish

“…The presence of TPH or TPH subtypes has been detected in different organs of several fish species, including the pineal organs of adult rainbow trout (Oncorhynchus mykiss) and pike (Esox lucius), 49 the hypothalamus of adult Atlantic croaker (Micropogonias undulatus), 50 and the brain and retina of zebrafish embryos. 51,52 In addition, the catabolic enzyme MAO has been found in fish species such as perch (Perca fluviatilis), 37 goldfish, 53 rainbow trout, 54,55 carp, 55 pike, 56 catfish (Ictalurus melas), 57 Atlantic croaker, 50 and zebrafish. 58 However, in contrast to the serotonergic system of terrestrial vertebrates, which features the two MAO types A and B, only one form of MAO has been detected in fish.…”

“…182 Both cell types were exposed to fluoxetine concentrations up to 140 µM (48.4 mg/L) for 24 h. The cell cultures were then analyzed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrasodium bromide tetrazolium (MTT) and 7-ethoxyresorufin-O-deethylase (EROD) assays. The MTT assays showed effective concentration (EC 50 ) values of 5 µM (1.73 mg/L) and 66 µM (22.8 mg/L) for PLHC-1 and PRTH, respectively, and the EROD assay resulted in an EC 50 value of 77 µM (26.6 mg/L) for PRTH. Changes in ROS levels were only determined for PLHC-1 cells.…”

The effects of prenatal PCBs on adult female paced mating reproductive behaviors in rats

“…Previously, PCBs and their metabolites were shown to impact neurotransmitter and steroid hormone systems underlying reproductive function (Khan and Thomas, 2001;Ptak et al, 2005;Seegal et al, 1985;Seegal et al, 2002;Tsai et al, 1997). These changes in turn are likely to have profound effects on reproductive behaviors.…”

“…PCBs and their metabolites can act at multiple nodes of the neuroendocrine axis: they may serve as hormone mimics (Connor et al, 1997), alter circulating hormone levels (Desaulniers et al, 1999), change patterns of estrous cyclicity (Meerts et al, 2004;Buitenhuis et al, 2004), disrupt hormone metabolism Kester et al, 2000;Yamane et al, 1975), influence endocrine-related and hypothalamic gene expression (Aluru et al, 2004;Bansal et al, 2005;Colciago et al, 2005;Flouriot et al, 1995;Gore et al, 2002;Pravettoni et al, 2005;Salama et al, 2003), interfere with hormone binding proteins (Brouwer and van den Berg, 1986;Chauhan et al, 2000), alter neuronal signaling to endocrine regions of the brain (Khan and Thomas, 2001;Morse et al, 1996;Seegal et al, 1985;Seegal et al, 1990) or indirectly affect steroid receptor availability via molecular crosstalk (Brunnberg et al, 2003;Pearce et al, 2004).…”