The purpose of this study was to examine whether perinatal exposure to two major environmental endocrine-disrupting chemicals, bisphenol A (BPA; 0.1 mg/kg/day orally) and nonylphenol [NP; 0.1 mg/kg/day (low dose) and 10 mg/kg/day (high dose) orally] daily from gestational day 3 to postnatal day 20 (transplacental and lactational exposures) would lead to behavioral alterations in the male offspring of F344 rats. Neither BPA nor NP exposure affected behavioral characteristics in an open-field test (8 weeks of age), in a measurement of spontaneous motor activity (12 weeks of age), or in an elevated plus-maze test (14 weeks of age). A passive avoidance test (13 weeks of age) showed that both BPA- and NP-treated offspring tended to delay entry into a dark compartment. An active avoidance test at 15 weeks of age revealed that BPA-treated offspring showed significantly fewer avoidance responses and low-dose NP-treated offspring exhibited slightly fewer avoidance responses. Furthermore, BPA-treated offspring significantly increased the number of failures to avoid electrical unconditioned stimuli within 5-sec electrical shock presentation compared with the control offspring. In a monoamine-disruption test using 5 mg/kg (intraperitoneal) tranylcypromine (Tcy), a monoamine oxidase inhibitor, both BPA-treated and low-dose NP-treated offspring at 22–24 weeks of age failed to show a significant increment in locomotion in response to Tcy, whereas control and high-dose NP-treated offspring significantly increased locomotion behavior after Tcy injection. In addition, when only saline was injected during a monoamine-disruption test, low-dose NP-treated offspring showed frequent rearing compared with the control offspring. The present results indicate that perinatal low-dose BPA or NP exposure irreversibly influenced the reception of fear-provoking stimuli (e.g., electrical shock), as well as monoaminergic neural pathways.

Growing evidence suggests that endocytic dysfunction is intimately involved in early stage Alzheimer disease pathology, such as the accumulation of ␤-amyloid precursor protein in enlarged early endosomes. However, it remains unclear how endocytic dysfunction is induced in an age-dependent manner. Cytoplasmic dynein, a microtubule-based motor protein, interacts with another microtubule-associated protein, dynactin. The resulting dynein-dynactin complex mediates minus enddirected vesicle transport, including endosome trafficking. We have previously shown that the interaction between dynein-dynactin complexes is clearly attenuated in aged monkey brains, suggesting that dynein-mediated transport dysfunction exists in aged brains. Our immunohistochemical analyses revealed that age-dependent endocytic pathology was accompanied by an increase in Rab GTPases in aged monkey brains. Here, we demonstrated that siRNA-induced dynein dysfunction reproduced the endocytic pathology accompanied by increased Rab GTPases seen in aged monkey brains and significantly disrupted exosome release. Moreover, it also resulted in endosomal ␤-amyloid precursor protein accumulation characterized by increased ␤-site cleavage. These findings suggest that dynein dysfunction may underlie age-dependent endocytic dysfunction via the up-regulation of Rab GTPases. In addition, this vicious circle may worsen endocytic dysfunction, ultimately leading to Alzheimer disease pathology.The appearance of neuronal endocytic pathology before senile plaque deposition suggests that endocytic dysfunction is involved in early stage Alzheimer disease (AD) 2 pathology, such as the accumulation of ␤-amyloid precursor protein (APP) in enlarged early endosomes (1-4). ␤-Amyloid protein (A␤), the major component of senile plaques, is produced from APP through sequential proteolytic cleavages by ␤-and ␥-secretases, and such amyloidogenic cleavage, so-called ␤-site cleavage, of APP can occur through the endocytic pathway (1, 3). These findings suggest that endocytosis is involved in APP metabolism, and its dysfunction may lead to AD pathology. However, it remains unclear how endocytic dysfunction is induced in an age-dependent manner.Cytoplasmic dynein is a microtubule-based motor protein required for minus end-directed axonal transport (5, 6). Dynactin, another microtubule-associated protein, binds to dynein intermediate chain (DIC) via its subunit, P150glued/ dynactin (DYN) to form dynein-dynactin complexes that mediate minus end-directed vesicle transport, which includes endosome trafficking (7-12). We have previously shown that the interaction between DIC and DYN is clearly attenuated in aged monkey brains, suggesting that aging may impair dyneinmediated transport (13). Other studies also support this idea (14 -17). Thus, in this study we investigated age-dependent endocytic pathology in cynomolgus monkey brains and tested our hypothesis of whether dysfunction of dynein causes endocytic dysfunction leading to AD pathology. Here, we demonstrated that siRNA-induced dysf...

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