Permanent defects in rat peripheral auditory function following perinatal hypothyroidism: determination of a critical period

Rats were treated with propylthiouracil (PTU) for 10-day periods beginning at different ages. Daily injections of L-thyroxine (T4) were administered concurrently with PTU to a group of rats which served as one control group. Peripheral auditory function was evaluated by the brainstem response audiometry (BSRA) technique performed at 12, 16, 25 and 120 days of age. PTU treatment significantly increased wave I latency (cochlear nerve compound action potential) in adult rats when administered from 3 days before delivery through 6 days of age, but was without permanent effect (wave I latencies and thresholds) when administered for 10 days starting at 10 days after birth. T4 replacement during the first 10 postnatal days prevented permanent abnormalities. These data suggest that the period of greatest vulnerability to thyroid hormone depletion in the peripheral auditory system extends from at least 3 days before delivery through between 5 and 10 days of age.     

Tyrosine hydroxylase and dopamine beta-hydroxylase inductions evoked by reserpine in the superior cervical ganglion of developing eu- and hypothyroid rats.

This study was designed to determine the effect of neonatally-produced hypothyroidism on reserpine-elicited tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (D beta H) induction in the superior cervical ganglion (SCG) in rats. Some rats were rendered hypothyroid from birth by daily treatment with propylthiouracil (PTU). Some hypothyroid rats received replacement therapy with triiodothyronine (T3). Some rats received PTU for 20 days, beginning at 90 days of age. Some rats were not treated and served as controls. TH and D beta H activities were assayed at 30, 50 and 110 days of age. Basal TH activity in the SCG for rats made hypothyroid as neonates was significantly lower than for controls at all ages tested; basal D beta H activity for these rats was lower than for controls at 30 and 50 days of age, but by 110 days was not different from that for controls. Basal TH activity for rats made hypothyroid as adults was intermediate between that for controls and rats made hypothyroid from infancy. Injecting control rats with reserpine produces a robust TH induction in the SCG at each age tested, and a strong D beta H induction at 50 and 110 days of age. Reserpine-evoked TH and D beta H inductions in rats made hypothyroid as adults were not different from those seen in controls. In contrast, rats made hypothyroid from infancy showed virtually no evidence of a reserpine-provoked TH or D beta H induction at any age tested. TH and D beta H inductions for hypothyroid rats given T3 replacement were completely normal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Auditory sensitivity in rats exposed to toluene and/or acetyl salicylic acid.

The present study investigates whether exposure to acetyl salicylic acid (ASA) affects the permanent auditory loss, caused by simultaneous exposure to toluene. Rats were exposed to toluene by inhalation (1,000 ppm), or to ASA by gavage (100 mg kg-1), or to both toluene and ASA, during 10 days. Toluene exposure caused a loss of auditory sensitivity recorded as auditory brainstem response, and no loss was found after exposure to ASA alone. The group exposed to both ASA and toluene had a more severe sensitivity loss (p < 0.05) at all frequencies compared with all other groups immediately after (2-5 days) exposure and also 4 months later. The results indicate that ASA permanently potentiates toluene induced loss of auditory sensitivity.     

Hypothyroidism alters antioxidant defence system in rat brainstem during postnatal development and adulthood

The present investigation was carried out to evaluate alterations in oxidative stress parameter [lipid peroxidation (LPx)] and antioxidant enzyme activities [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)] in rat brainstem in response to neonatal hypothyroidism during development (from birth to 7, 15 and 30 days old) and adulthood (90 days old). Hypothyroidism in rats was induced by feeding the lactating mothers (from the day of parturition till weaning, 25 days old) or directly to the pups with 0.05 % [6-n-propyl 2-thiouracil (PTU)] in drinking water. Increased level of LPx was observed in brainstem of 7 days old hypothyroid rats, accompanied by augmented activities of SOD and GPx. In 15 and 30 days old hypothyroid rat brainstem, a significant decline in LPx was observed. Significantly increased activities of CAT and GPx were observed in 15 and 30 days PTU-treated rats. Decreased level of LPx was observed in brainstem of rats treated with PTU from birth to 30 days followed by withdrawal up to 90 days of age (transient hypothyroidism) as compared to control and persistent treatment of PTU up to 90 days of age. Activities of CAT and GPx were decreased in persistent hypothyroid rats of 90 days old with respect to control and transient hypothyroid rats. On the other hand, SOD activity was decreased in both persistent and transient hypothyroid rats with respect to control rats. These results suggest that the PTU-induced neonatal hypothyroidism modulates the antioxidant defence system during postnatal development and adulthood in brainstem of rats.     

Effects of perinatal Kepone exposure on sexual differentiation of the rat brain

Timed-pregnant Sprague-Dawley rats were injected intraperitonealy with Kepone dissolved in sesame oil on alternate days beginning on day 18 of gestation and extending through day 7 of lactation with doses of 10 or 5 mg/kg. At 7 days of age the neurologic development of the pups was assessed using the following tests: day of eye opening, occurrence of auditory startle, righting response, reflex suspension, tactile forelimb-placing response, negative geotaxis, and open-field activity. At 70 days of age, vaginal washes from female offspring were examined microscopically for evidence of cyclic activity. At 120 days of age, animals were sacrificed and the brains were examined histologically and the volume of the medial preoptic nucleus was determined. The results indicated that exposure of rat pups to Kepone via either placental and/or milk transfer can result in an acute, or transient, impairment of neurologic development and a possible permanent neuroendocrine impairment. The permanent neuroendocrine dysfunction may be similar to the androgenization phenomenon (i.e., female pups exposed to sex steroids during development) and thus may be related to the reported estrogenic properties of Kepone.     

Postnatal development of auditory function in the chicken revealed by auditory brain-stem responses (ABRs)

Auditory evoked brain-stem responses (ABRs) were recorded from the surfaces of the brain of lightly anesthetized newborn (1-7 days old) and adult (7-9 weeks old) chickens as a measure of the development of auditory processing. One-day-old and older chickens showed a series of waves within 5 msec after the stimulus onset. This precocity of the ABR in chickens contrasts with the first appearance of the ABR in cats at 4 days of age. The ABR onset latency was shorter in adult chickens than in newborns. This indicates that developmental modifications of mechanical transmission in the external and middle ear or cytodifferentiation of the sensory hair cells of the basillar papilla and the neurons of the acoustic nerve continue postnatally. Within the complex wave form of the response, most of the inter-wave latencies decreased with maturation, indicating that development of the central auditory pathway also continues postnatally. One inter-wave latency (N1 to P3-4) was significantly shorter (P less than 0.05) in adults than in newborns for intense click stimuli, and even among newborns, this inter-wave latency was significantly shorter in 6- and 7-day-old specimens than in 1-3-day-old specimens. It seems likely that changes in the N1 to P3-4 inter-wave latency reflect changes in evoked activity of second order auditory neurons that are located in the nucleus angularis and nucleus magnocellularis, and that intensive developmental changes occur in these neurons during the first postnatal week. The ABR recorded in chickens is a reliable measure of functional activity in the auditory system which is reproducible between individuals and capable of demonstrating developmental changes in specific segments of the wave form.     

Postnatal lead exposure induces supersensitivity to the stimulus properties of a D2-D3 agonist.

To examine the impact of lead (Pb) exposure during the ontogeny of dopaminergic (DA) systems on resultant DA function, rats were exposed postnatally (0-21 days of age) via the lactating dam to 0, 100 or 350 ppm Pb acetate in drinking water. At 2 months of age, the postnatally Pb-exposed rats were trained to discriminate the stimulus properties of either the D1 receptor agonist SKF38393 (6.0 mg/kg) or the D2-D3 receptor family subtype agonist quinpirole (0.05 mg/kg) from saline using a standard two-lever operant food-reinforced drug discrimination paradigm. In each training group, dose-effect curves describing drug lever responding to lower doses of the training drug and to preadministration of selective DA antagonists were obtained to examine Pb-induced changes in DA sensitivity, and doses of non-DA compounds were substituted to determine the specificity of any changes in DA sensitivity. In the D1/saline training condition, Pb exposure was not associated with any specific or consistent changes in DA sensitivity. In contrast, exposure to Pb was associated with D2-D3 receptor subtype supersensitivity as was indicated by significantly elevated levels of drug lever responding in the presence of quinpirole and haloperidol and to at least one dose of apomorphine. No differences in the dose-effect curves for either (+)-amphetamine or NMDA were observed in the D2-D3-trained control and Pb-exposed groups, but an increase in drug lever responding in the presence of pentobarbital was noted in the Pb-exposed group relative to control. Taken together, these findings are consistent with a Pb-induced functional D2-D3 supersensitivity possibly mediated via autoreceptors. Moreover, this functional D2-D3 supersensitivity necessarily represents a permanent effect of postnatal Pb exposure since both blood and brain Pb levels were negligible at the time drug discrimination training began.     

Maturation of the visual evoked response in the dog

Dogs 1–28 days of age were exposed to flashes of white light and the visual evoked response (VER) recorded by means of topical scalp electrodes. The earliest VER was a long-latency negative wave which appeared at 10 days postnatally. The electroretinogram (ERG) was also recorded and a small negative wave appeared at 10 days postnatally. At day 14, the short-latency negative wave of the VER appeared. A double-negative wave was then present at day 14. The b-wave of the ERG was first recordable at day 15, and at day 16 the positive-negative complex of the VER was first observed. The latencies of the VER progressively decreased from day 16 to day 28 as did those of the ERG.     

Prognostic significance of multimodality evoked response testing in high-risk newborns

Exposure to hypoxic-ischemic events in fetal or neonatal life may lead to permanent brain damage and subsequent neurodevelopmental deficits. Clinical and diagnostic tools have been somewhat helpful in identifying an at-risk group, particularly those patients sustaining significant neurologic sequelae. In this prospective study, the prognostic significance of multimodality evoked responses in high-risk newborns was examined. A group of 44 high-risk newborns, as well as 14 healthy newborns, were tested during the newborn period with auditory brainstem responses and somatosensory evoked responses; these tests were repeated at 2 and 6 months corrected age. A neonatal neurologic examination, the Einstein Neonatal Neurobehavioral Assessment Scale, was also conducted. At 1 year corrected age, both groups were assessed in a blind fashion by a pediatric neurologist and a psychologist to determine neurodevelopmental outcome. Results indicated that somatosensory evoked response abnormalities in particular predict an abnormal neurologic status at 1 year of age. Abnormalities that persisted or worsened correlated with severe neurologic impairment, whereas an abnormal somatosensory evoked response that improved or normalized in infancy was associated with mild to moderate neurologic sequelae. Increased brainstem conduction in the auditory brainstem responses was also associated with neurologic sequelae. Normal findings from auditory brainstem responses and somatosensory evoked responses predicted normal developmental scores in all areas, as well as a normal neurologic outcome at 1 year with negative predictive powers ranging from 85–100%. Evoked response testing appears to be an important adjunct to the neurologic investigation of high-risk newborns.     

Mild carbon monoxide exposure and auditory function in the developing rat

We have examined the influence of chronic mild exposure to carbon monoxide (CO) on cognitive (learning) and auditory function in the developing rat. We have demonstrated that the auditory pathway is compromised at exposures less than 50 ppm, whereas learning was not influenced at 100 ppm. Artificially reared rat pups were exposed to CO during the brain growth spurt and onset of myelination. Spatial learning was assessed using the Morris Water Maze and three tests of auditory function: (1) auditory brainstem conduction times; (2) the amplitude of the eighth nerve's action potential; and (3) otoacoustic emissions carried out on rat pups (age 22- 24 days). The pups were gastrostomy-reared on a rat milk substitute and chronically exposed to CO at discrete concentrations in the range of 12-100 ppm from 6 days of age to post-weaning at 21-23 days of age. We found no difference in auditory brainstem conduction times at all CO concentrations in comparison to non-exposed controls. There was a difference in otoacoustic emissions for test and controls at CO concentrations of 50 ppm but not at lower concentrations. There was a consistent attenuation of the amplitude of the eighth nerve's action potential, even at the lowest CO exposure examined. The attenuation of the amplitude of the action potential of the eighth nerve at 50 ppm carbon monoxide exposure did not completely recover by 73 days of age. We conclude that prolonged mild exposure to carbon monoxide during development causes measurable functional changes at the level of the eighth cranial nerve.     

Delayed development of GFA immunoreactivity in the parietal cortex during thyroid hormone deficiency

The influence of neonatal hypothyroidism on the development of immunoreactivity to glial fibrillary acidic protein (GFA) was studied in parietal cortex of rats treated from birth with the antithyroid agent propylthiouracil (PTU) for 3 or 8 weeks. Density of GFA immunoreactivity was evaluated in cryostate sections reacted with an antiserum specific for GFA. Three weeks postnatally, the density of GFA-immunoreactive structures in the cortical layers II-V was 70% lower in PTU-treated animals than in controls injected with the solvent. This marked difference between the groups was, however, not seen in either the molecular layer, layer VI or white matter. The inhibited development of GFA immunoreactivity was not persistent in animals treated with PTU for 8 weeks continuously. Plasma from animals treated with PTU for 1,2,3 and 8 weeks was collected and the TSH level in each group compared with samples from age-matched controls and newborn pups. The treatment with PTU resulted in a more than 10-fold increase in TSH level after 1 week of injections. In longterm groups of 8 weeks, the TSH level decreased in the PTU-treated animals, but stayed considerably higher than control values throughout the experiments.The results described in the present paper indicate a thyroid hormone dependent development of the GFA immunoreactivity in cortex cerebri astrocytes.     

Long-lasting abolishment of noradrenaline induced stimulation of oxidative metabolism after chronic exposure of developing mouse astrocytes to cocaine.

Rate of 14CO2 production from [l-14C]glutamate was determined as a measurement of oxidative metabolism in developing primary cultures of astrocytes, obtained from the neonatal mouse brain and grown in the absence (control) or presence of cocaine. From the age of 3 days, the drug-exposed cultures were grown in a tissue culture medium containing either 1 or 3 microM cocaine. After 2 months of chronic exposure to cocaine the metabolic rate showed an increase of approximately 50%, but there was a long lag period (several weeks) before this response occurred. In contrast to a marked stimulation of CO2 production when noradrenaline was added to untreated cultures of the same age, there was no similar effect of noradrenaline on cultures treated with cocaine. After exposure to cocaine for 21 days (24-day-old cultures), both the enhanced CO2 production and the abolishment of the normal response to noradrenaline persisted during 'withdrawal' (cessation of drug exposure) throughout the total period investigated, i.e. to an age of 60 days (corresponding to a withdrawal period of 36 days). The correlation of these findings with in vivo data is discussed.     

Bilirubin induces auditory neuropathy in neonatal guinea pigs via auditory nerve fiber damage

Bilirubin can cause temporary or permanent sensorineural deafness in newborn babies with hyperbilirubinemia. However, the underlying targets and physiological effects of bilirubin‐induced damage in the peripheral auditory system are unclear. Using cochlear functional assays and electron microscopy imaging of the inner ear in neonatal guinea pigs, we show here that bilirubin exposure resulted in threshold elevation in both compound action potential (CAP) and auditory brainstem response (ABR), which was apparent at 1 hr and peaked 8 hr after drug administration. The threshold elevation was associated with delayed wave latencies and elongated interwave intervals in ABR and CAP. At 72 hr postinjection, these measures returned to control levels, except for the CAP amplitude. Cochlear microphonics remained unchanged during the experiment. Morphological abnormalities were consistent with the electrophysiological dysfunction, revealing fewer auditory nerve fibers (ANFs) in the basal turn, myelin sheath lesions of spiral ganglion neurons (SGNs) and ANFs, and loss of type 1 afferent endings beneath inner hair cells (IHCs) without loss of hair cells at 8 hr posttreatment. Similar to the electrophysiological findings, morphological changes were mostly reversed 10 days after treatment, except for the ANF reduction in the basal turn. These results suggest that hyperbilirubinemia in neonatal guinea pigs impaired auditory peripheral neuromechanisms that targeted mainly the IHC synapses and the myelin sheath of SGNs and their fibers. Our observations indicate a potential connection between hyperbilirubinemia and auditory neuropathy. © 2012 Wiley Periodicals, Inc.     

Sensory and motor characterization in the postnatal valproate rat model of autism

Although autism is diagnosed according to three core features of social deficits, communication impairments, and repetitive or stereotyped behaviors, other behavioral features such as sensory and motor impairments are present in more than 70% of individuals with autism spectrum disorders (ASD). Exposure of rat pups to the teratogen valproate during sensitive periods of brain development has been shown to elicit behavioral features associated with autism diagnosis and has been proposed as a valid animal model of the disorder. The purpose of this study was to characterize sensory and motor performance in rats postnatally treated with valproate. Thirty-four rat pups were injected with either valproate (150 mg/kg) or saline on postnatal days 6-12. Auditory and tactile startle as well as auditory sensory gating was assessed during both the juvenile and adolescent stages of development; motor testing was conducted during late adolescence and included a sunflower seed eating task and a vermicelli handling task. Valproate-treated rats were underresponsive to auditory stimuli, showed deficits in auditory sensory gating, and demonstrated impairments in motor speed and performance. These findings suggest that postnatal valproate treatment elicits sensory and motor features often seen in individuals with ASD. Further, the hyposensitivity seen in postnatally valproate-treated rats contrasted with hypersensitivity previously reported in prenatally valproate-exposed rats. This suggests that timing of teratogenic exposure during early brain development may be important to consider when investigating the neurobiological basis of sensorimotor impairments in ASD.     

Sub-optimal function of the auditory brainstem in term infants with transient low Apgar scores.

OBJECTIVES: To assess functional integrity of the auditory brainstem in neonates with transient low Apgar scores. METHODS: Forty-two term infants were studied with brainstem auditory evoked response (BAER) using the maximum length sequence during the first month of life. All had transient low Apgar scores but no clinical signs of hypoxic-ischaemic encephalopathy (HIE). RESULTS: The latencies of BAER waves I and III in these infants were similar to those of age-matched normal controls at all click rates (91/s, 227/s, 455/s and 910/s) during the period studied. Wave V latency was increased at 910/s on day 1 (P<0.01), but did not differ from that in the controls on any other days. I-V interval was increased significantly at 455/s and 910/s on day 1 (P<0.01 and 0.001) and day 3 (P<0.05 and 0.01). On days 5 and 7, BAER wave latencies and intervals were similar to those in the controls. On day 30, all latencies and intervals reached the values in the controls. No abnormalities were seen in BAER wave amplitude variables on any days. CONCLUSIONS: Neonates with transient low Apgar scores but without HIE had a significant increase in I-V interval at very high click rates on the first three days of life. SIGNIFICANCE: Brainstem auditory function is sub-optimal during the first few days in neonates with transient low Apgar scores.     

Rehabilitation from neonatal hypothyroidism: spontaneous motor activity, exploratory behavior, avoidance learning and responses of pituitary--thyroid axis to stress in male rats

Long-Evans male rats were made hypothyroid from birth by the addition of 6-N-propylthiouracil (PTU) to their drinking water (0.1%). A group of animals was rehabilitated beginning at postnatal day 25 by withdrawal of the PTU from the drinking water. Subsequently, the rats were tested for a variety of behavioral tasks. Serum concentrations of thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) were determined by radioimmunoassay. At 50 days of age, PTU-treated rats had non-detectable levels of T4 but an eight-fold increase of TSH. In 50-day-old, neonatally hypothyroid but rehabilitated rats, serum TSH and T3 were normal, although T4 was still significantly lower. At 90 days of age, basal levels of TSH and thyroid hormones were normal in the rehabilitated rats, but thyroid hormone secretion in response to various types of neural stress was markedly altered. Comparison of passive avoidance learning revealed no significant alteration in the memory retention of either PTU-treated or rehabilitated animals. The 50-day-old, rehabilitated rats showed increased locomotor activity both in running-wheel and in hole-board tests; this hyperactivity, though markedly reduced, still persisted at day 90. In the early phase of rehabilitation (50 days of age), decreases in exploratory activity and lack of habituation occurred with the hole-board test; by the late phase of rehabilitation (90 days of age) these behavioral parameters had become normal. These results suggest generally longer periods of plasticity of the brain and better prospects for rehabilitation from neonatal cretinoid retardation than commonly believed. Specifically, the pituitary-thyroid system and neural mechanisms integrating adaptive behavior possess considerable capacity for spontaneous recovery from hypothyroidism; certain types of altered neuroendocrine and behavioral responses appear to be less amenable to rehabilitation or require longer periods for complete rehabilitation.     

A case of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), showing temporary improvement during the treatment with eicosapentaenoic acid ethyl ester]

We report a 67-year-old man with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), successfully treated with eicosapentaenoic acid ethyl ester (EPA-E) for about eight months. He showed bilateral auditory disturbance and slowly progressive gait ataxia at age 50 during treatment of diabetes mellitus (DM) with subcutaneous injection of insulin since age 29. At age 58 he manifested an acute hemiparesis of right extremities for one week with no abnormal findings on neuroradiological examinations. A permanent pacemaker was implanted at age 61 to treat frequent syncopal attacks due to complete atrioventricular block. On admission to our hospital, neurological examinations revealed dementia, auditory disturbance, severe cerebellar ataxia and mild atrophy of proximal muscles with systemic hyporeflexia. Based on a point mutation in position 3243 of mitochondrial DNA, he was diagnosed as having MELAS with severe DM, auditory disturbance and cardiac conduction block. After initiation of treatment with EPA-E at a dose of 2,700 mg/day he showed temporarily an improvement in auditory disturbance, blood glucose control and cerebellar ataxia. In objective evaluations for cerebellar ataxia, we could find significant decreases in times for 20 m walking and heel-knee patting in the ninth month, and in time for tracing of a whirl from the third to the ninth month, compared with those before treatment of EPA-E (p < 0.0001). Because EPA-E is taken into mitochondrial membranes and activates electron transmission enzyme complexes, it might be a candidate for therapy of mitochondrial encephalomyopathy, including MELAS.     

The alcohol‐sensitive period during early octavolateral organ development in zebrafish (Danio rerio)

Fetal alcohol exposure can cause Fetal Alcohol Spectrum Disorders (FASD), completely preventable developmental disabilities characterized by permanent birth defects. However, specific gestational timing when developing organs are most sensitive to alcohol exposure is unclear. In this study, we examined the temporal effects of embryonic alcohol exposure on octavolateral organs in zebrafish (Danio rerio ), including inner ears and lateral line neuromasts that function in hearing, balance, and hydrodynamic detection, respectively. To determine an alcohol‐sensitive period in the first 24 hours post fertilization (hpf), Et(krt4:EGFP)^sqet4 zebrafish that express green fluorescent protein in sensory hair cells were treated in 2% alcohol for 2, 3, and 5‐hours. Octavolateral organs of control and alcohol‐exposed larvae were examined at 3, 5, and 7 days post fertilization (dpf). Using confocal and light microscopy, we found that alcohol‐exposed larvae had significantly smaller otic vesicles and saccular otoliths than control larvae at 3 dpf. Only alcohol‐exposed larvae from 12‐17 hpf had smaller otic vesicles at 5 dpf, smaller saccular otoliths at 7 dpf and fewer saccular hair cells, neuromasts and hair cells per neuromast at 3 dpf. In addition, auditory function was assessed by microphonic potential recordings from inner ear hair cells in response to 200‐Hz stimulation. Hearing sensitivity was reduced for alcohol‐exposed larvae from 7‐12 and 12‐17 hpf. Our results show that 12‐17 hpf is an alcohol‐sensitive time window when morphology and function of zebrafish octavolateral organs are most vulnerable to alcohol exposure. This study implies that embryonic alcohol exposure timing during early development can influence severity of hearing deficits. © 2017 Wiley Periodicals, Inc.     

Neuroprotective effects of cutamesine,a ligand of the sigma‐1 receptor chaperone,against noise‐induced hearing loss

The sigma‐1 receptor, which is expressed throughout the brain, provides physiological benefits that include higher brain function. The sigma‐1 receptor functions as a chaperone in the endoplasmic reticulum and may control cell death and regeneration within the central nervous system. Cutamesine (1‐(3,4‐dimethoxyphenethyl)?4‐(3‐phenylpropyl) piperazine dihydrochloride) is a ligand selective for this receptor and may mediate neuroprotective effects in the context of neurodegenerative disease. We therefore assessed whether cutamesine protects the inner ear from noise‐induced or aging‐associated hearing loss. Immunohistochemistry and Western blotting revealed that the sigma‐1 receptor is present in adult cochlea. We treated mice with 0, 3, or 30 mg/kg cutamesine from 10 days before noise exposure until the end of the study. All subjects were exposed to a 120‐dB, 4‐kHz octave‐band noise for 2 hr. We assessed auditory thresholds by measuring the auditory‐evoked brainstem responses at 4, 8, and 16 kHz, prior to and 1 week, 1 month, or 3 months following noise exposure. For the aging study, measurements were made before treatment was initiated and after 3 or 9 months of cutamesine treatment. Damage to fibrocytes within the cochlear spiral limbus was assessed by quantitative histology. Cutamesine significantly reduced threshold shifts and cell death within the spiral limbus in response to intense noise. These effects were not dose or time dependent. Conversely, cutamesine did not prevent aging‐associated hearing loss. These results suggest that cutamesine reduces noise‐induced hearing loss and cochlear damage during the acute phase that follows exposure to an intense noise. © 2015 Wiley Periodicals, Inc.     

The alterations in CNS serotonergic mechanisms caused by neonatal chlorpyrifos exposure are permanent

Fetal or neonatal exposure to chlorpyrifos (CPF) or related organophosphate pesticides leads to abnormalities of brain cell development, synaptic function, and behavior. Recent studies in rats indicate profound effects on serotonin (5HT) systems that originate during CPF exposure and that are still present at 2 months posttreatment in the young adult. To determine if these changes are permanent, we administered 1 mg/kg of CPF daily to neonatal rats on postnatal days 1-4, a regimen devoid of systemic toxicity, and examined 5HT synaptic markers at 5 months of age: radioligand binding to 5HT1A and 5HT2 receptors and to the 5HT transporter. There were global elevations in all three synaptic proteins, with pronounced sex selectivity (effects on males>females) and a regional hierarchy of effects, viz. striatum>midbrain approximately brainstem>cerebral cortex. Because there is a normal sex disparity for 5HT synaptic proteins, with females having higher values than males, the increase caused by CPF exposure in males completely eliminated this difference. Our findings at 5 months of age replicate those seen in young adulthood and strongly suggest that the effects of neonatal CPF exposure on 5HT systems are permanent.