Aroclor 1254 inhibits tryptophan hydroxylase activity in rat brain

Abstract

Previous studies have shown that oral exposure of rats to polychlorinated biphenyls (PCBs) results in reduced 5-hydroxytryptamine (5-HT) concentrations in certain brain regions. In the present study, we investigated whether the PCB mixture Aroclor 1254 (0.33 mg/g body weight as a single oral dose) can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in 5-HT synthesis, and reduce 5-HT concentrations in selected brain areas. In two separate experiments, Aroclor 1254 exposure consistently reduced TPH activity in the brainstem (7.2 and 8.7%), frontal cortex (17.4 and 14.8%), and hypothalamus (10.7 and 9.4%) without altering the rats' food intake or growth. Moreover, Aroclor 1254 accumulation in the frontal cortex demonstrated a negative correlation with TPH activity (correlation coefficient -0.82). In addition, 5-HT concentrations decreased in the brainstem and frontal cortex after Aroclor 1254 exposure by 9.1 and 19.7%, respectively. These results suggest that the Aroclor 1254-induced decreases in 5-HT concentrations in certain areas of the rat brain are due to inhibition of TPH activity, similar to our recent observations in Atlantic croaker, and that TPH is one of the targets of PCB neurotoxicity in both fish and mammals.

The Recreational Drug Ecstasy Disrupts the Hypothalamic-Pituitary-Gonadal Reproductive Axis in Adult Male Rats

“…Our results are consistent with observations that environmental or pharmaceutical substances that disrupt monoaminergic neurotransmitter functions in the hypothalamus, including pesticides [56, 57] and PCBs [58, 59], affect GnRH and LH release. The popularity of MDMA among humans has increased in recent years [1], leading to concern over the potential health hazards associated with recreational drug use.…”

Estrogenic environmental endocrine-disrupting chemical effects on reproductive neuroendocrine function and dysfunction across the life cycle

“…In addition, the rate-limiting step in serotonin synthesis, tryptophan hydroxylation, was significantly inhibited through decreased enzymatic activity of TPH in the hypothalamus. As mentioned earlier, studies in the pubertal male rat showed similar effects of A1254 treatment on the biosynthesis of serotonin [53]. Individual PCBs also affect gonadotropin levels.…”

“…Among these neurotransmitters is serotonin, which modulates LH secretion through actions on hypothalamic GnRH neurons [52]. Activity of the ratelimiting enzyme in serotonin synthesis, tryptophan hydroxylase (TPH) was reduced in the hypothalamus of pubertal male rats acutely exposed to A1254 [53], suggesting that the stimulatory effect of serotonin on GnRH-induced LH secretion may be disrupted by PCB inhibition of TPH. Other neurotransmitter systems may be similarly affected by PCBs, which have been shown to alter dopaminergic neurotransmission, among others, in puberty and adulthood [54].…”

PCB congener-specific disruption of reproductive neuroendocrine function in Atlantic croaker

“…Evidence has accumulated that polychlorinated biphenyls (PCBs) impair the function of serotonergic and other monoaminergic neurotransmitter systems in vertebrate brains (Seegal, 1996;Khan and Thomas, 2004). PCBs reduce serotonin (5-hydroxytryptamine; 5-HT) concentrations and increase the metabolite (5-hydroxyindolacetic acid, 5-HIAA) to 5-HT ratio both in rats (Seegal, 1996;Chu et al, 1996) and in the Atlantic croaker, Micropogonias undulatus (Khan and Thomas, 1997).…”