Association Between Fenvalerate-Induced Endocrine Disruption In Developing Brain And Impairments In Cognitive & Behavioral Development In Mice

Pubertal period is a critical period for cognitive and behavioral development. It has been well established that testosterone (T) and estrogen (E) are de novo synthesized in the developing brain. These steroid hormones play an important role in sexual differentiation of brain and development of cognition and behavior. There are growing evidences suggesting that endocrine disrupting chemicals (EDCs) can interfere with the processes of sexual differentiation of brain, beginning with steroid hormone changes, and extending to disruptions in behavioral development. Fenvalerate is a potential EDC. The purpose of this study was to examine the impairments in cognitive and behavioral development in mice exposed to fenvalerate during puberty, and to investigate the effects of pubertal fenvalerate exposure on the synthesis of T and E₂ and the expression of androgen receptor (AR) and estrogen receptors (ERs) in cerebral cortex. In addition,, this study was to explore whether there was an association between fenvalerate-induced endocrine disruption in the developing brain and the impairments in cognitive and behavioral development.1. Effects of pubertal fenvalerate exposure on cognitive and behavioral developmentTo investigate the effects of pubertal fenvalerate exposure on cognitive and behavioral development, mice were orally administered with either vehicle or fenvalerate (7.5 or 30 mg/kg/day) from postnatal day (PND) 28 to PND56. Behavioral tests were performed to assess learning and memory, aggressive performance, anxiety-related activities, and sensorimotor function. Results showed that escape latency and swim distance were significantly longer than controls in females, as determined by Morris water maze. In addition, time proportion of objective quadrant and times of crossing objective quadrant were significantly decreased in females. Interestingly, the sex difference on escape latency, swim distance, time proportion of objective quadrant and times of crossing objective quadrant, observed in controls, was diminished or eliminated by fenvalerate. By contrast, pubertal fenvalerate exposure resulted in sex difference on swim speed, whereas no sex difference on swim speed was observed in controls. These results suggested that pubertal fenvalerate exposure impaired spatial cognition and memory in a gender-specific manner, that is, the impairment is more serious in females than in males. In aggressive behavior test, latency was much longer. Inaddition, contact time was much shorter in mice treated with 30 mg/kg of fenvalerate, suggesting puberty exposure to fenvalerate might inhibit aggression in male mice. There was different tendency on peripheral time between males and females in open test, that is, peripheral time was significantly increased in female mice treated with fenvalerate, but decreased in the male mice treated with fenvalerate. Interestingly, there was a sex difference on peripheral time in controls, which was also eliminated by fenvalerate. Horizontal score was significantly different in male mice, but not in females. In addition, neither control mice nor mice treated with 7.5 mg/kg fenvalerate was observed sex difference in tightrope score, but sex difference in tightrope score was observed in mice treated with 30 mg/kg fenvalerate. Take together, pubertal fenvalerate exposure impaired cognitive function and behavioral development in a gender-specific manner.2. Effects of pubertal fenvalerate exposure on endocrine disruptor in developing brainTo investigate the effects of pubertal fenvalerate exposure on the synthesis of T and E₂ and the expression of AR and ERs in cerebral cortex, cerebral cortex was collected. Result showed that the level of T and E₂ in cerebral cortex was significantly decreased in males exposed to fenvalerate, and was significantly increased in females exposed to fenvalerate. In agreement with the decrease in T and E₂ syntheses, the expression of 17-hydroxysteroid dehydrogenase (17β-HSD), a key enzyme for T synthesis, was significantly reduced in cerebral cortex of fenvalerate-exposed males. Conversely, in females, the level of T and E₂ was mildly increased. Correspondingly, the expression of 17β-HSD in cerebral cortex was mildly up-regulated by fenvalerate. Pubertal fenvalerate exposure had no effect on the expression of steroidogenic acute regulatory protein (StAR), P450 17α-hydroxylase enzyme (P45017α) and P450 side-chain cleavage enzyme (P450scc), the key enzymes for T synthesis, and P450 aromatase (CYP19), the key enzyme for E₂ synthesis, in cerebral cortex of males and females. Interestingly, the expression of AR in cerebral cortex was up-regulated in male and female mice exposed to fenvalerate, whereas pubertal fenvalerate exposure did not affect the level of ERαand ERβin cerebral cortex. Taken together, these results suggest that pubertal fenvalerate exposure disrupts T and E₂ synthesis and the expression of AR in cerebral cortex.In summary, the present results allow us to reach the following conclusions. Firstly, pubertal fenvalerate exposure impairs cognitive function and behavioral development in a gender-specific manner. Secondly, pubertal fenvalerate exposure disrupts T and E₂ synthesis and the expression of AR in cerebral cortex. Finally, endocrine disruptor in development brain contributes, at least partially, to fenvalerate-induced impairement on cognitive and behavioral development.