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OBJECTIVES: Craniosynostosis is a devastating disorder characterized by premature closure of the cranial plates before or shortly after birth. This results in an abnormally shaped skull, face, and brain. Little is known about hearing disorders in such patients, and nothing has been published about their auditory brainstem responses. Our objective was to evaluate such patients for auditory brainstem response and hearing disorders with the long-term goal of improving patient evaluation and management. PATIENTS AND METHODS: We evaluated the auditory brainstem responses, hearing, and brain images of children with fibroblast growth factor receptor 2 craniosynostosis (n = 11). RESULTS: Prolongation of the auditory brainstem response I-to-III interpeak latency was a frequent characteristic of fibroblast growth factor receptor 2 craniosynostosis, occurring in 91% of our patients. Prolongation of the III-to-V interpeak latency was an occasional characteristic, occurring in 27% of our patients. Whenever the I-to-III interpeak latency was prolonged, wave II was always abnormal. Associated morbidities included sensorineural hearing loss (27%), recurrent otitis media (100%), and Arnold-Chiari malformation (27%). Cranial decompression improved the interpeak latencies of 2 children. CONCLUSIONS: These previously undocumented auditory brainstem response abnormalities reflect abnormal neural transmission, which could cause peripheral and central auditory processing disorders. We speculate that the major pathogenic basis of the I-to-III interpeak latency and wave II abnormalities is compression of the auditory nerve as it passes through the internal auditory meatus and posterior fossa, which would explain the auditory nerve hearing loss, tinnitus, and vertigo that affect these children. Awareness of these abnormalities could lead to important advancements in the auditory and neurosurgical assessment and management of this overlooked patient group. We provide recommendations for the improved assessment and management of these patients. In particular, we recommend that auditory brainstem response diagnostics become standard clinical care for this patient group as the best way to detect auditory nerve compression. [ABSTRACT FROM AUTHOR]

Xenia2 is a DV cluster actinobacteriophage that infects Gordonia rubripertincta NRRL B-16540. The genome is 68,135bp, has a GC content of 57.9% and 98 predicted protein-coding genes, 33 of which have a predicted function. Xenia2 has a lysis cassette with an endolysin (lysin A) and four different holin-like transmembrane proteins., Competing Interests: The authors declare no conflict of interest.

Objectives: We previously demonstrated that a mild pre-natal/early post-natal iron-deficient anaemic (IDA) diet devoid of long-chain polyunsaturated fatty acids (LC-PUFA) affected development, neurophysiology, and cerebral lipid biochemistry of the guinea pigs' progeny. Impacts of dietary LC-PUFA on altered cerebral development resulting from pre-natal IDA are unknown. To address this health issue, impacts of mild gestational IDA in the presence of dietary LC-PUFA on the offsprings' neural maturation were studied in guinea pigs using auditory brainstem responses (ABRs) and assessments of brain fatty acids (FAs)., Methods: Female guinea pigs (n = 10/group) were fed an iron sufficient (IS) or IDA diet (146 and 12.7 mg iron/kg, respectively) with physiological amounts of LC-PUFA, during the gestation and lactation periods. From post-natal day (PNd) 9 onwards, the IS + PUFA diet was given to both groups of weaned offspring. Cerebral tissue and offsprings' ABR were collected on PNd24., Results: There was no difference in peripheral and brainstem transmission times (BTTs) between IS + PUFA and IDA + PUFA siblings (n = 10/group); the neural synchrony was also similar in both groups. Despite the absence of differences in auditory thresholds, IDA + PUFA siblings demonstrated a sensorineural hearing loss in the extreme range of frequencies (32, 4, and 2 kHz), as well as modified brain FA profiles compared to the IS + PUFA siblings., Discussion: The present study reveals that siblings born from dams exposed to a moderate IDA diet including balanced physiological LC-PUFA levels during pregnancy and lactation demonstrate minor impairments of ABR compared to the control siblings, particularly on the auditory acuity, but not on neural synchrony, auditory nerve velocity and BTT.

Maternal care is an indispensable component of offspring survival and development in all mammals and necessary for reproductive success. Although brain areas regulating maternal behaviors are innervated by serotonergic afferents, very little is known about the role of this neurotransmitter in these behaviors. To evaluate the contribution of serotonin to maternal care, we used mice with a null mutation in the gene for tryptophan hydroxylase-2 (TPH2), which results in a genetic depletion of brain serotonin, and tested them in a wide range of maternal behavior paradigms. We found that litters born to and reared by TPH2(-/-) mothers showed decreased survival, lower weaning weights and increased cannibalization. In addition, TPH2(-/-) mothers performed poorly in pup retrieval, huddling, nest construction and high-arched back nursing. Aggression in TPH2(-/-) dams was not triggered by lactation and was steadily high. Survival and weaning weight deficits of TPH2(-/-) pups were rescued by cross-fostering and in litters of mixed genotype (TPH2(-/-) and TPH2(-/+) ). However, the maternal behaviors of TPH2(-/-) dams did not improve when rearing either TPH2(+/+) pups or mixed-genotype litters. In addition, TPH2(-/-) pups significantly worsened the behavior of TPH2(+/+) dams with respect to cannibalism, weaning weight and latency to attack. Olfactory and auditory functions of TPH2(-/-) females or anxiety-like behaviors did not account for these maternal alterations as they were equal to their TPH2(+/+) counterparts. These findings illustrate a profound influence of brain serotonin on virtually all elements of maternal behavior and establish that TPH2(-/-) pups can engender maladaptive mothering in dams of both genotypes., (© 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Objectives: It is well known that postnatal/early childhood iron deficiency (ID) anaemia (IDA) adversely affects infants' cognitive development and neurophysiology. However, the effects of IDA during gestation and lactation on the offspring are largely unknown. To address this health issue, the impact of mild IDA during gestation and lactation on the offsprings' neural maturation was studied in the guinea pig, using auditory brainstem responses (ABRs) latencies and amplitudes., Methods: Female guinea pigs (n = 10/group) were fed an iron sufficient (ISD) or deficient diet (IDD) (144 and 11.7 mg iron/kg) during the gestation and lactation periods. From postnatal day (PNd) 9 onward, the ISD was given to both groups of weaned offspring. The offsprings' ABRs were collected on PNd24 using a broad range of stimulus intensities in response to 2, 4, 8, 16, and 32 kHz tone pips., Results: Although the IDA siblings (n = 8) did not differ in brainstem transmission times (BTTs) compared to the IS siblings (n = 8), they showed significant delayed peak I latency at 100 and 80 dB, respectively. Additionally, significantly higher ABR wave amplitudes were observed in the IDA female offspring between 35 and 50 dB (4 kHz), a phenomenon suggestive of a neural hyperactivity (hyperacusis)., Discussion: In support to our previous findings, the present results indicate that a mild IDA during gestation and lactation can have detrimental effects on early development of the offsprings' hearing and nervous systems, particularly on neural synchrony and auditory nerve conduction velocity, but not on BTT.

'Ecstasy' or 3,4-methylenedioxy-N-methamphetamine (MDMA) is an amphetamine abused for its euphoric, empathogenic, hallucinatory, and stimulant effects. It is also used to treat certain psychiatric disorders. Common settings for Ecstasy use are nightclubs and "rave" parties where participants consume MDMA and dance to loud music. One concern with the club setting is that exposure to loud sounds can cause permanent sensorineural hearing loss. Another concern is that consumption of MDMA may enhance such hearing loss. Whereas this latter possibility has not been investigated, this study tested the hypothesis that MDMA enhances noise-induced hearing loss (NIHL) by exposing rats to either MDMA, noise trauma, both MDMA and noise, or neither treatment. MDMA was given in a binge pattern of 5 mg/kg per intraperitoneal injections every 2 h for a total of four injections to animals in the two MDMA-treated groups (MDMA-only and Noise + MDMA). Saline injections were given to the animals in the two non-MDMA groups (Control and Noise-only). Following the final injection, noise trauma was induced by a 10 kHz tone at 120 dB SPL for 1 h to animals in the two noise trauma-treated groups (Noise-only and Noise + MDMA). Hearing loss was assessed by the auditory brainstem response (ABR) and cochlear histology. Results showed that MDMA enhanced NIHL compared to Noise-only and that MDMA alone caused no hearing loss. This implies that "clubbers" and "rave-goers" are exacerbating the amount of NIHL when they consume MDMA and listen to loud sounds. In contrast to earlier reports, the present study found that MDMA by itself caused no changes in the click-evoked ABR's wave latencies or amplitudes., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Fetal alcohol syndrome (FAS) is a leading cause of neurodevelopmental impairments (NDIs) in developed countries. Sensory deficits can play a major role in NDI, yet few studies have investigated the effects of prenatal alcohol exposure on sensory function. In addition, there is a paucity of information on the lifelong effects of prenatal alcohol exposure. Thus, we sought to investigate the effects of prenatal alcohol exposure on auditory function across the life span in an animal model. Based on prior findings with prenatal alcohol exposure and other forms of adverse prenatal environments, we hypothesized that animals prenatally exposed to alcohol would show an age-dependent pattern of (i) hearing and neurological abnormalities as postweanling pups, (ii) a substantial dissipation of such abnormalities in young adulthood, and (iii) a resurgence of such abnormalities in middle-aged adulthood., Methods: Pregnant rats were randomly assigned to an untreated control (CON), a pair-fed control (PFC), or an alcohol-treated (ALC) group. The ALC dams were gavaged with 6 mg/kg alcohol daily from gestation day (GD) 6 to 21. The PFC dams were gavaged daily from GD6 to GD21 with an isocaloric and isovolumetric water-based solution of maltose-dextrins and pair-fed to the ALC dams. The CON dams were the untreated group to which the ALC and CON groups were compared. Hearing and neurological functions in the offspring were assessed with the auditory brainstem response (ABR) at the postnatal ages of 22, 220, and 520 days., Results: In accord with our hypothesis, ABR abnormalities were first observed in the postweanling pups, largely dissipated in young adulthood, and then resurged in middle-aged adulthood. This age-related pattern suggests that the ALC pups had a developmental delay that dissipated in young adulthood and an enhanced age-related deterioration that occurred in middle-aged adulthood. Such a pattern is consistent with the fetal programming hypothesis of adult-onset diseases (the Barker hypothesis)., Conclusions: Our findings have important clinical implications for the assessment and management of (i) childhood hearing disorders and their comorbidities (i.e., speech-and-language, learning, and attention deficit disorders) and (ii) enhanced age-related hearing and neurological degeneration in middle-aged adulthood that can result from prenatal alcohol exposure. We recommend hearing evaluation be a part of any long-term follow-up for FAS patients and patients exposed to any adverse prenatal environment., (Copyright © 2011 by the Research Society on Alcoholism.)

Introduction: This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g)., Results: BAER latencies of 751-1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501-750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results., Discussion: The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management., Methods: Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.

Antenatal corticosteroid (AC) treatment is given to pregnant women at risk for preterm birth to reduce infant morbidity and mortality by enhancing lung and brain maturation. However, there is no accepted regimen on how frequently AC treatments should be given and some studies found that repeated AC treatments can cause growth retardation and brain damage. Our goal was to assess the dose-dependent effects of repeated AC treatment and estimate the critical number of AC courses to cause harmful effects on the auditory brainstem response (ABR), a sensitive measure of brain development, neural transmission and hearing loss. We hypothesized that repeated AC treatment would have harmful effects on the offspring's ABRs and growth only if more than 3 AC treatment courses were given. To test this hypothesis, pregnant Wistar rats were given either a high regimen of AC (HAC), a moderate regimen (MAC), a low regimen (LAC), or saline (SAL). An untreated control (CON) group was also used. Simulating the clinical condition, the HAC dams received 0.2mg/kg Betamethasone (IM) twice daily for 6 days during gestation days (GD) 17-22. The MAC dams received 3 days of AC treatment followed by 3 days of saline treatment on GD 17-19 and GD 20-22, respectively. The LAC dams received 1 day of AC treatment followed by 5 days of saline treatment on GD 17 and GD 18-22, respectively. The SAL dams received 6 days of saline treatment from GD 17 to 22 (twice daily, isovolumetric to the HAC injections, IM). The offspring were ABR-tested on postnatal day 24. Results indicated that the ABR's P4 latencies (neural transmission time) were significantly prolonged (worse) in the HAC pups and that ABR's thresholds were significantly elevated (worse) in the HAC and MAC pups when compared to the CON pups. The HAC and MAC pups were also growth retarded and had higher postnatal mortality than the CON pups. The SAL and LAC pups showed little or no adverse effects. In conclusion, repeated AC treatment had harmful effects on the rat offspring's ABRs, postnatal growth and survival. The prolonged ABR latencies reflect slowed neural transmission times along the auditory nerve and brainstem auditory pathway. The elevated ABR thresholds reflect hearing deficits. We concluded that repeated AC treatment can have harmful neurological, sensory and developmental effects on the rat offspring. These effects should be considered when weighing the benefits and risks of repeated AC treatment and when monitoring and managing the prenatally exposed child for possible adverse effects., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Iron deficiency (ID) anemia (IDA) adversely affects different aspects of the nervous system such as myelinogenesis, neurotransmitters synthesis, brain myelin composition, and brain fatty acid and eicosanoid metabolism. Infant neurophysiological outcome in response to maternal IDA is underexplored, especially mild to moderate maternal IDA. Furthermore, most human research has focused on childhood ID rather than prenatal or neonatal ID. Thus, our study evaluated the consequences of mild maternal IDA during pregnancy and lactation on the offsprings' auditory function using the auditory brainstem response (ABR). This technique provides objective measures of auditory acuity, neural transmission times along the peripheral and brainstem portions of the auditory pathway, and postnatal brain maturation. Female guinea pigs (n = 10/group) were fed an iron sufficient diet (ISD) or an iron deficient diet (IDD) (144 and 11.7 mg iron/kg) during their acclimation, gestation, and lactation periods. From postnatal d (PNd) 9 onward, the ISD was given to all weaned offspring. ABR were collected from the offspring on PNd24 using a broad range of stimulus intensities in response to 2, 4, 8, 16, and 32 kHz tone pips. IDA siblings (n = 4), [corrected] compared with the IS siblings (n = 5), had significantly elevated ABR thresholds (hearing loss) in response to all tone pips. These physiological disturbances were primarily due to a sensorineural hearing loss, as revealed by the ABR's latency-intensity curves. These results indicate that mild maternal IDA during gestation and lactation altered the hearing and nervous system development of the young offspring.

Our objective was to assess the effects of repeated antenatal corticosteroid treatments on the neonatal auditory brainstem response (ABR), a sensitive measure of neonatal brain maturity and auditory function. To achieve this, we performed and blindly evaluated neonatal ABRs on a subset of infants delivering within a multicenter randomized placebo-controlled clinical trial comparing single versus repeated courses of antenatal corticosteroid treatments for women at 23-31 weeks gestation who remained at increased risk for preterm birth. The women were randomly assigned to either the single or the repeated antenatal corticosteroid treatment group. Women in the repeated antenatal corticosteroid group received weekly antenatal corticosteroid treatments until 34 weeks gestation or until they reached a study-determined limited number of courses, whereas women in the single antenatal corticosteroid group received an initial course of corticosteroid followed by weekly placebo injections. We performed ABR testing on their infants prior to discharge. The latencies of waves I, III and V and the peak-to-trough amplitudes of waves I and V were compared between those in the single (n=27) and repeated antenatal corticosteroid treatment (n=24) groups. The majority of repeated antenatal corticosteroid infants (20 of 24) were exposed to ≥ 4 antenatal corticosteroid treatments. Even though gestational age was similar between our subset of single and repeated antenatal corticosteroid treatment groups, infant birth weight and length and head circumference were significantly smaller in the repeated antenatal corticosteroid group (p <0.05). Despite these differences in birth sizes, there were no significant group differences in the ABR wave latencies or amplitudes. We concluded that our repeated antenatal corticosteroid treatments, in comparison to a single treatment, did not significantly benefit or harm the neonatal ABR despite significant effects on birth size., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Consuming omega-3 fatty acids (omega-3 FA) during pregnancy and lactation is beneficial to fetal and infant development and might reduce the incidence and severity of preterm births by prolonging pregnancy. Consequently, supplementing maternal diets with large amounts of omega-3 FA is gaining acceptance. However, both over- and under-supplementation with omega-3 FA can harm offspring development. Adverse fetal and neonatal conditions in general can enhance age-related neural degeneration, shorten life span and cause other adult-onset disorders. We hypothesized that maternal over- and under-nutrition with omega-3 FA would shorten the offspring's life span and enhance neural degeneration in old adulthood. To test these hypotheses, female Wistar rats were randomly assigned to one of the three diet conditions starting from day 1 of pregnancy through the entire period of pregnancy and lactation. The three diets were Control omega-3 FA (omega-3/omega-6 ratio approximately 0.14), Excess omega-3 FA (omega-3/omega-6 ratio approximately 14.5) and Deficient omega-3 FA (omega-3/omega-6 ratio approximately 0% ratio). When possible, one male and female offspring from each litter were assessed for life span and sensory/neural degeneration (n=15 litters/group). The Excess offspring had shorter life spans compared to their Control and Deficient cohorts (mean+/-SEM=506+/-24, 601+/-14 and 585+/-21 days, p

This study was designed to investigate the effects of high and low n-3 FA feeding during perinatal period on the growth and FA profiles in the Wistar rat offspring. Female rats were randomized into three diet groups during pregnancy and lactation (L): Control (CON, ratio of n-3/n-6 approximately 0.14, n=24); n-3 FA deficient (LOW, ratio of n-3/n-6 approximately 0, n=31) and n-3 FA excess (HIGH, ratio of n-3/n-6 approximately 14.0, n=23). Milk samples were obtained on L14. After L24, all offspring were fed the control diet until killed at 23-25 weeks of age. There were no group differences in maternal weight gains or offspring birth weights. After birth, the HIGH offspring weighed the least while CON offspring the most. The FA profiles of the CON and LOW milk resembled CON diet, and the HIGH milk resembled HIGH diet. Body FA profiles of males from all groups were similar to the CON milk profile, but the CON and LOW females resembled the CON milk, while the HIGH females resembled the HIGH milk. All HIGH offspring had increased n-3 levels and n-3/n-6 ratios (males: 0.16+/-0.01; females: 0.23+/-0.06). Thus LOW dams likely had maternal body fat mobilization that compensated for the deficiency in dietary n-3 FA, while a compensatory mechanism was not observed when intake was high. Excess amount of n-3 FA affected female offspring more than males. These data indicate the long-lasting effects of supplementation and supplementing high amounts of n-3 FA during pregnancy and lactation may not be advisable.

Consuming omega-3 fatty acids (omega-3 FA) during pregnancy and lactation benefits fetal and infant brain development and might reduce the severity of preterm births by prolonging pregnancy. However, diets that are relatively rich in omega-3 FA can adversely affect fetal and infant development and the auditory brainstem response (ABR), a measure of brain development and sensory function. We previously examined the offspring of female rats fed excessive, adequate or deficient amounts of omega-3 FA during pregnancy and lactation. The 24-day-old offspring in the Excess group, compared to the Control group, had postnatal growth retardation and poor hearing acuity and prolonged neural transmission times as evidenced by the ABR. The Deficient group was intermediate. The current study followed these offspring to see if these poor outcomes persisted into young adulthood. Based on prior findings, we hypothesized that the Excess and Deficient offspring would "catch-up" to the Control offspring by young adulthood. Female Wistar rats received one of the three diet conditions from day 1 of pregnancy through lactation. The three diets were the Control omega-3 FA condition (omega-3/omega-6 ratio approximately 0.14), the Excess omega-3 FA condition (omega-3/omega-6 ratio approximately 14.0) and Deficient omega-3 FA condition (omega-3/omega-6 ratio approximately 0% ratio). The Control diet contained 7% soybean oil; whereas the Deficient and Excess omega-3 FA diets contained 7% safflower oil and 7% fish oil, respectively. One male and female offspring per litter were ABR-tested as young adults using tone pip stimuli of 2, 4, 8 and 16 kHz. The postnatal growth retardation and prolonged neural transmission times in the Excess and Deficient pups had dissipated by young adulthood. In contrast, the Excess group had elevated ABR thresholds (hearing loss) at all tone pip frequencies in comparison to the Control and Deficient groups. The Deficient group had worse ABR thresholds than the Control group in response to the 8 kHz tone pips only. The Excess group also had ABR amplitude-intensity profiles suggestive of hyperacusis. These results are consistent with the Barker hypothesis concerning the fetal and neonatal origins of adult diseases. Thus, consuming diets that are excessively rich or deficient in omega-3 FA during pregnancy and lactation seems inadvisable because of risks for long-lasting adverse effects on brain development and sensory function.

Omega-3 fatty acids (omega-3 FA) consumption during pregnancy and lactation is beneficial to fetal and infant growth and may reduce the severity of preterm births. Thus, scientists and clinicians are recommending increasingly higher omega-3 FA doses for pregnant women and nursing babies for advancing the health of preterm, low birth weight, and normal babies. In contrast, some studies report that over-supplementation with omega-3 FA can have adverse effects on fetal and infant development by causing a form of nutritional toxicity. Our goal was to assess the effects of omega-3 FA excess and deficiency during pregnancy and lactation on the offspring's neural transmission as evidenced by their auditory brainstem responses (ABR). Female Wistar rats were given one of three diets from day 1 of pregnancy through lactation. The three diets were the Control omega-3 FA condition (omega-3/omega-6 ratio approximately 0.14), the Deficient omega-3 FA condition (omega-3/omega-6 ratio approximately 0%) and the Excess omega-3 FA condition (omega-3/omega-6 ratio approximately 14.0). The Control diet contained 7% soybean oil, whereas the Deficient diet contained 7% safflower oil and the Excess diet contained 7% fish oil. The offspring were ABR-tested on postnatal day 24. The rat pups in the Excess group had prolonged ABR latencies in comparison to the Control group, indicating slowed neural transmission times. The pups in the Excess group also showed postnatal growth restriction. The Deficient group showed adverse effects that were milder than those seen in the Excess group. Milk fatty acid profiles reflected the fatty acid profiles of the maternal diets. In conclusion, excess or deficient amounts of omega-3 FA during pregnancy and lactation adversely affected the offspring's neural transmission times and postnatal thriving. Consuming either large or inadequate amounts of omega-3 FA during pregnancy and lactation seems inadvisable because of the potential for adverse effects on infant development.

Consumption of the nutrients omega-3 fatty acids (omega-3 FA) during pregnancy and lactation is considered beneficial to fetal and infant development. It may also reduce the incidence and severity of preterm births by prolonging gestational length. However several recent human and animal studies have reported that over-supplementation with omega-3 FA, especially in the form of fish oil, can have adverse effects on fetal and infant development and the auditory brainstem response (ABR). Our goal was to assess further the effects of omega-3 FA excess and deficiency during pregnancy and lactation on the offspring's auditory acuity as evidenced by their ABR thresholds. Female Wistar rats were given diets that were either deficient, adequate (control) or excess in omega-3 FA from day 1 of pregnancy through lactation. The offspring were ABR-tested at the postnatal age of 24 days. The rat pups in the Excess treatment condition had significantly elevated (worse) ABR thresholds, postnatal growth restriction, and a trend for increased postnatal mortality in comparison to the Control group. The Deficient group was intermediate. In conclusion, excess or deficient amounts of omega-3 FA during pregnancy and lactation in the laboratory rat adversely affected the offspring's auditory acuity. Postnatal thriving was also adversely affected. Consuming or administering large or inadequate amounts of omega-3 FA during pregnancy and lactation seems inadvisable because of the potential for adverse effects on infant development.

Background: Biomarkers of fetal exposure to alcohol are important to establish so that early detection and intervention can be made on these infants to prevent undesirable outcomes. The aim of this study was to analyze long-chain fatty acid ethyl esters (FAEEs) in meconium as potential biomarkers of fetal alcohol exposure and effect., Methods: Fatty acid ethyl esters were analyzed in the meconium of 124 singleton infants by positive chemical ionization gas chromatography/mass spectrometry (GC/MS) and correlated to maternal ethanol use., Results: A total of 124 mother/infant dyads were enrolled in the study: 31 were in the control group and 93 were in the alcohol-exposed group. The incidence (28% vs 9.7%, p = 0.037) of ethyl linoleate detected in meconium was significantly higher in the alcohol-exposed groups than the control groups. Similarly, when the concentrations of ethyl linoleate in meconium were grouped (trichotomized), there was a significant linear by linear association between alcohol exposure and group concentrations of ethyl linoleate (p = 0.013). Furthermore, only alcohol-exposed infants were found in the group with the highest ethyl linoleate concentration. The sensitivity of ethyl linoleate in detecting prenatal alcohol exposure was only 26.9%, and its specificity and positive predictive value were 96.8 and 96.2%, respectively. There was no significant correlation between the concentration of ethyl linoleate in meconium and absolute alcohol consumed (oz) per drinking day across pregnancy, although a trend toward a positive correlation is seen at lower amounts of alcohol consumed. Among the polyunsaturated, long-chain FAEEs, there was weak evidence that the incidence (21.5% vs 6.5%, p = 0.057) and concentration (p = 0.064) of ethyl arachidonate (AA) were significantly higher in the alcohol-exposed groups than the control groups. Ethyl linolenate and ethyl docosahexanoate (DHA) in meconium were found only in the alcohol group, although not at statistically significant levels. Highly significant correlations were found among the concentrations of ethyl linoleate, ethyl linolenate, ethyl AA, and ethyl DHA in meconium (correlations ranged between rs = 0.203, p = 0.024; and rs = 0.594, p < 0.001)., Conclusion: We conclude that FAEEs in meconium, particularly ethyl linoleate and ethyl AA, are biomarkers of high specificity for prenatal exposure to alcohol in newborn infants. We also propose that ethyl AA and DHA could be potential biomarkers of fetal alcohol effects on the developing fetal brain and should be investigated further.

Chemoprotective agents reduce the toxic side effects of chemotherapy agents such as cisplatin. The conventional belief is that the chemoprotective agent WR-2721 (Amifostine), while protecting against most cisplatin-induced side effects, does not protect against cisplatin-induced ototoxicity (i.e., hearing loss). There is no knowledge, however, about the efficacy of high doses of WR-2721 (WR) in possibly protecting against cisplatin-induced ototoxicity. Thus, the dose-dependent effects of WR in possibly ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 18, 40, 80, or 400 mg/kg/injection of the rescue agent WR ( n = 5 or 10/group). Other groups received either 80 mg/kg/injection WR alone ( n = 5) or were untreated ( n = 14). Ototoxicity was assessed by auditory brain stem responses (ABR). WR provided dose-dependent rescue from cisplatin's ototoxicity with no protection at the low dose of 18 mg/kg, moderate protection at 40 mg/kg, and nearly complete protection at 80 and 400 mg/kg. However, WR doses of 40 mg/kg or higher caused neurotoxicity as evidenced by prolongations in the ABR's interpeak latencies. Thus, high doses of WR provided the beneficial effect of protecting against cisplatin-induced ototoxicity, but had the harmful side effect of neurotoxicity. Previous failures to find chemoprotection from cisplatin-induced ototoxicity were likely due to the use of WR doses that were too small. The clinical implications of the beneficial and harmful effects of high doses of WR are discussed.

Laboratory rats prenatally exposed to alcohol, nicotine, amphetamine, undernutrition or hypoxia can exhibit shortened life span and other signs of enhanced age-related degeneration. We evaluated the possibility of similar effects following prenatal cocaine exposure. Pregnant rats received 20 or 40 mg/kg cocaine HCl subcutaneously (C20, C40), twice daily, from gestation days (GD) 7-20. Untreated control (UTC) and pair-fed control (PFC) groups were also used. The pregnant C40, C20, and PFC dams ate less food and gained less weight than the UTC dams did. The pregnant C40 and C20 dams drank more water than the UTC dams did, and the pregnant PFC dams drank less than the UTC dams did. The C40 and PFC offspring had delayed earflap openings. The C40 male and female offspring had lower birth weights than their cohorts in the other three groups. The C40 female and male offspring remained significantly underweight until postnatal day (PND) 28 and PND56, respectively. During young adulthood, the males and females in the C20, C40, and PFC groups had normal body weights. During old adulthood, however, the C20 and C40 males and the C20, C40, and PFC females developed reduced body weights as compared with their UTC cohorts. The C20 and C40 male offspring and the C20, C40, and PFC female offspring also had life spans that were 7-12% shorter than that of their UTC cohorts. Thus, groups that showed reduced body weights in old age also showed shorter life spans. These results provided converging evidence that prenatal cocaine exposure caused enhanced age-related degeneration. Observations on cardiac and other organ pathology were also made. Health implications for children born to cocaine-abusing women are discussed.

Tinnitus is one of the consequences of cisplatin chemotherapy, but its underlying mechanisms are not well understood. Since it has been shown that cisplatin causes outer hair cell loss, it is possible that loss of these cells might induce tinnitus by increasing spontaneous activity in the central auditory system. To test this possibility, the present study examined the effects of cisplatin treatment on cochlear hair cells and on spontaneous neural activity in the dorsal cochlear nucleus of hamsters. Recordings, carried out approximately 1 month after cisplatin treatment, demonstrated significant increases in spontaneous activity across broad regions of the dorsal cochlear nucleus relative to levels in saline-treated controls. Histological results showed that cisplatin-treated animals also displayed dramatic loss of outer hair cells over most of the basal turn of the cochlea. Inner hair cells remained intact, although some evidence of damage to their stereocilia was evident. These findings indicate that cisplatin treatment causes abnormalities in spontaneous activity in the dorsal cochlear nucleus that are associated with widespread damage to outer hair cells. However, since some damage to inner hair cells was also observed, the role of inner hair cell injury in contributing to higher spontaneous activity cannot be ruled out.

The illicit use of cocaine has increased dramatically over the last 10-12 years. There has been a corresponding increase in cocaine abuse among obstetric patients and in the number of "cocaine babies." According to some estimates, these children make up more than half of the drug-associated births. This problem is therefore a major public health concern. Consequently, our laboratory investigated the effects of prenatal cocaine exposure on hearing, vision, growth, and exploratory/stress behavior. This chapter summarizes the literature on animals and humans on these topics and presents new observations from our laboratory. In terms of maternal toxicity, prenatal cocaine exposure causes hypertension, placental abruption, spontaneous abortion, poor pregnancy weight gain, and undernutrition secondary to appetite suppression. Some offspring effects include in utero growth retardation, cephalic hemorrhage, fetal edema, altered body composition, congenital malformations, and even pre- and postnatal death. The offspring can also exhibit a variety of behavioral, visual, hearing, and language disorders. Differential effects of animal strain and late gestational cocaine exposure are discussed. Comparisons are made between prenatal cocaine, the fetal alcohol syndrome, and the effects of prenatal undernutrition. Recommendations for clinical assessment and intervention are made.

Alcohol exposure and undernutrition during pregnancy have been associated with altered fetal body composition. Recent observations suggest that cocaine exposure during pregnancy may impair delivery of nutrients to the fetus and could thereby alter body growth and composition. Such effects are important because they can adversely influence physical and neural development. Consequently, we investigated the dose-dependent effects of cocaine on fetal body composition in an animal (rat) model and compared such effects with those caused by prenatal alcohol exposure and undernutrition. Pregnant Sprague-Dawley rats received either 20, 30, 40, or 50 mg/kg cocaine HCl (SC) twice daily from gestation days 7 through 19. Pair-fed (undernutrition) and untreated control groups and a group receiving 3.0 g/kg alcohol (PO) twice daily served as comparison groups (n = 11 to 14/group). Females were sacrificed on gestation day 20. One male and one female fetus was removed from each dam. The fetuses were minced, dehydrated, defatted, and analyzed for content of protein and the minerals Zn, Ca, Fe, Mg, K, and Na. In terms of concentration per unit of fat-free dry solids, male fetuses in the cocaine groups showed significant decreases in protein compared to untreated controls (15+/-3 to 20+/-2 mg/g vs. 24+/-4 mg/g, p = 0.01). There was a significant treatment effect for Ca (p < 0.05), reflecting a trend for decreased Ca concentrations in the fetuses of the cocaine and undernutrition groups. Male fetuses in the alcohol group had significantly elevated Mg levels compared to male fetuses in the other groups (3.0+/-0.8 vs. 1.0+/-0.2 to 2.3+/-0.7 mg/g, p < 0.05). There were some sex differences, with female fetuses having significantly lower concentrations of Mg, Fe, K, and higher protein concentrations than male fetuses. Although the effects were few and modest, these results suggest that prenatal cocaine, alcohol, and undernutrition can differentially alter fetal body weight and composition and, therefore, adversely influence fetal development.

Fetal alcohol syndrome (FAS) refers to a pattern of anomalies that include craniofacial, CNS, growth, and various sensory anomalies. We have observed that FAS is associated with four kinds of hearing disorders: (1) developmentally delayed auditory function, (2) sensorineural hearing loss, (3) intermittent conductive hearing loss owing to recurrent serous otitis media, and (4) central hearing loss. As is the case with other syndromes associated with craniofacial anomalies and hearing impairments, speech and language pathologies also are common in FAS patients. Although auditory and vestibular systems arise from similar embryological tissue, vestibular dysfunction is variable in FAS. Early identification and intervention to treat hearing, language, and speech problems should improve the functional level of FAS in children.

The purpose of this investigation was to study the ameliorating effects of four agents on cisplatin-induced ototoxicity. Hamsters were given a series of five cisplatin injections either alone or in combination with sodium thiosulfate (STS), diethyldihydrothiocarbamate (DDTC), and S-2(3-aminopropylamino) ethylphosphorothioic acid (WR-2721), or fosfomycin. Ototoxicity was assessed anatomically by quantifying the extent of cochlear damage with the scanning electron microscope and physiologically with measures of the auditory brain stem response. When administered alone, cisplatin induced widespread loss of outer hair cells (OHCs) along much of the cochlea in the hamster, especially in the basal and middle turns, with an average survival of only 56% of the OHC population. In contrast, inner hair cells resisted cisplatin ototoxicity in the hamster. Thus the ameliorative effects of the different test agents were assessed by counting the number of surviving OHCs in each treatment group and comparing with cisplatin-treated controls. STS provided the most effective protection against the ototoxic effects of cisplatin, yielding 91% survival of OHCs. DDTC also reduced the ototoxic effects of cisplatin, yielding 68% survival of OHCs. Cotreatment with WR-2721 and fosfomycin yielded 45% and 52% OHC survival, respectively, and thus did not provide any chemoprotection. The results closely paralleled those based on auditory brain stem response recordings in that the magnitude of threshold shift was proportional to the amount of OHC loss; also, the amount of threshold shift at each frequency was in good agreement with the pattern of hair cell loss along the cochlear spiral. Thus both histologic and physiologic results suggest that STS and DDTC hold promise for ameliorating the ototoxic effects of cisplatin chemotherapy.

Fetal alcohol syndrome (FAS) is characterized in part by mental impairment, as well as craniofacial and ocular anomalies. These conditions are traditionally associated with childhood hearing disorders, because they all have a common embryonic origin in malformations of the first and second branchial arches, and have similar critical periods of vulnerability to toxic insult. A review of human and animal research indicates that there are four types of hearing disorders associated with FAS. These are: (1) a developmental delay in auditory maturation, (2) sensorineural hearing loss, (3) intermittent conductive hearing loss due to recurrent serous otitis media, and (4) central hearing loss. The auditory and vestibular systems share the same peripheral apparatuses (the inner ear and eighth cranial nerve) and are embryologically and structurally similar. Consequently, vestibular disorders in FAS children might be expected. The evidence for vestibular dysfunction in FAS is ambiguous, however. Like other syndromes associated with craniofacial anomalies, hearing disorders, and mental impairment, FAS is also characterized by a high prevalence of speech and language pathology. Hearing disorders are a form of sensory deprivation. If present during early childhood, they can result in permanent hearing, language, and mental impairment. Early identification and intervention to treat hearing, language, and speech disorders could therefore result in improved outcome for the FAS child. Specific recommendations are made for intervention and future research.

Fetal alcohol syndrome (FAS) is characterized by congenital anomalies traditionally associated with hearing disorders. The present study sought to (a) evaluate possible central hearing loss; (b) verify and extend previous observations on sensorineural and conductive hearing losses; (c) evaluate possible vestibular disorders; (d) examine the relationships between hearing, speech, language, vestibular, and dentofacial disorders in FAS patients; and (e) evaluate the influence of patient age, race, and gender on the expression of these morbidities. A biracial group of 22 FAS patients (aged 3 to 26 years) were evaluated by standard hearing, speech, language, and vestibular tests. Dentofacial and other malformations were also assessed. Of the 22 FAS patients, 17 (77%) had intermittent conductive hearing loss due to recurrent serous otitis media that persisted from early childhood into adulthood, whereas 6 (27%) had sensorineural hearing loss in addition to the conductive hearing loss. Among the 12 patients tested for central hearing function, all (100%) were significantly impaired. Among the patients tested for speech and language ability, 18 of 20 (90%) had speech pathology, 16 of 21 (76%) had expressive language deficits, and 18 of 22 (82%) had receptive language deficits. Hearing, speech, and language deficits were not influenced by age, race, or gender. On the vestibular tests, all performed within normal limits with the possible exception of one child (n = 6). High incidences of dentofacial, temporomandibular joint, ocular, cardiac, and skeletal disorders were observed. Race and gender tended to influence dental malocclusion class. Two subjects exhibited autistic tendencies. In conclusion, new and important findings included a high prevalence of sensorineural, conductive, and central hearing deficits, the persistence of otitis proneness into adulthood, the existence of temporomandibular joint disorders, and the possible influence of gender or race on dental malocclusions. Such disorders can contribute to the learning, behavioral, and emotional difficulties seen in FAS patients and warrant early, aggressive intervention.

Objective: Cocaine-associated morbidities in pregnant women (e.g., abruptio placentae, hypertension, seizures) occur mostly during the final stages of gestation. The purpose of our study was to determine whether cocaine's toxicity and blood levels varied as a function of "critical periods" of exposure during gestation., Study Design: To evaluate mortality rates, pregnant Long-Evans rats received subcutaneously 30, 40, or 50 mg/kg cocaine hydrochloride twice daily (C30, C40, and C50 groups) either during gestational days 7 to 13 (midgestation) or gestational days 14 to 20 (late gestation) (n 9 to 20 per group). Serum levels of the cocaine metabolite benzoylecgonine were examined in other groups of rats on either gestational day 13 (mid) or day 20 (late) in the C30 treatment condition (n = 5 and 10 per group)., Results: There were no maternal mortalities in the midgestation groups at any dose. In contrast, the late-gestation groups showed a dramatic dose-dependent effect, with maternal mortality rates of 0%, 40%, and 72% in the C30, C40, and C50 groups. The late-gestation group had higher benzoylecgonine levels than the midgestation groups did., Conclusions: Late gestation was associated with higher maternal mortality rates and higher benzoylecgonine levels, indicating that some underlying physiologic change enhanced cocaine's toxicity as pregnancy progressed. This increased sensitivity to cocaine may be mediated by estrogen or progesterone, suggesting that the cocaine-abusing woman is at increased risk for cocaine-induced morbidities whenever levels of these hormones are elevated, such as during the final stages of pregnancy or possibly when taking oral contraceptives.

Prenatal cocaine exposure is associated with disrupted state control and lowered activity levels. Prenatal retinoic acid excess also influences activity levels in laboratory rats. Activity level is usually monitored during a brief period in young offspring. The effects of these drugs on pup activity levels throughout the day is unknown. There is also little information on the long-lasting effects of these teratogens in adult animals. We compared the daily activity of rats which were prenatally exposed to cocaine or retinoic acid (RA). Appropriate control groups were also used. The offspring were evaluated for activity levels in a neophobic situation and for a 22-h period in same-sex groups of 3 littermates. As both pups and adults, the cocaine groups were hypoactive while the RA group was hyperactive when first placed into the testing cage (neophobic situation). Similarly, during the remainder of the 22-h testing period, the pup and adult cocaine animals exhibited reduced activity levels while the RA animals exhibited elevated activity levels. Thus, prenatal cocaine and retinoic acid exposures affected offspring activity levels differently, both drugs have long-lasting neurobehavioral effects that persist into adulthood, and effects are influenced by time-of-day. Strain-dependent differences and mechanisms of action are discussed.

This study investigated select aspects of peripheral and central auditory dysfunction, as well as the pathological effects of aging, In an animal model of fetal alcohol syndrome (FAS). Pregnant rats consumed liquid alcohol diets containing 0, 17.5, or 35% ethanol-derived calories, from gestation day 7 to parturition. A fourth group was untreated. Offspring of these mothers were tested for auditory and neurological function, using the auditory brainstem response at 6, 12, and 18 months of age. Some animals in the alcohol-exposed groups showed a peripheral auditory disorder in the form of congenital sensorineural hearing loss. This was correlated with punctate lesions and malformed stereocilia on the auditory sensory receptor cells of the inner ear. Alcohol-exposed animals also showed a central auditory processing disorder characterized by prolonged transmission of neural potentials along the brainstem portion of the auditory pathway. Animals in the highest dose group also showed an augmentation in the age-related deterioration of auditory acuity. Thus, increased peripheral and central auditory dysfunctions and pathological deterioration of auditory function in old age may be sequelae of FAS. Such morbidities have important implications for the long-term clinical assessment and management of FAS patients.

Pregnant rats received either 20, 30, 40, or 50 mg/kg cocaine HCl (SC) twice daily from gestation days 7 through 19. Pair-fed and untreated control groups and a group receiving 3.0 g/kg alcohol (PO) twice daily served as comparison groups. Females were sacrificed on gestation day 20 and the fetuses examined. Maternal weight gain and food consumption showed dose-dependent decreases. Maternal water consumption, by contrast, was significantly increased in the cocaine-treated animals and may reflect a diuretic effect. The maternal mortality rates in Sprague-Dawley rats were less than in two strains of Long-Evans rats, suggesting important strain-dependent differences in susceptibility to cocaine toxicity. Cocaine caused a significant dose-dependent decrease in fetal weights. Physical anomalies in the cocaine-exposed and alcohol-exposed fetuses included occasional hemorrhaging, edema, anophthalmia, and limb reduction. Despite increased maternal water consumption by cocaine-treated dams, there were no increases in fetal body water content. There were, however, significant decreases in fetal body fat content in the pair-fed, alcohol-treated, and two highest cocaine-treated groups.

Retinitis pigmentosa is the name given to a heterogeneous group of hereditary retinal degenerations characterized by progressive visual field loss, pigmentary changes of the retina, abnormal electroretinograms, and, frequently, night blindness. In this study, we investigated a family with dominant cone-rod degeneration, a variant form of retinitis pigmentosa. We used microsatellite markers to test for linkage to the disease locus and excluded all mapped autosomal loci. However, a marker from the short arm of the X chromosome, DXS989, showed 0% recombination to the disease locus, with a maximum lod (log-odds) score of 3.3. On the basis of this marker, the odds favoring X-linked dominant versus autosomal dominant inheritance are > 10(5):1. Haplotype analysis using an additional nine microsatellite markers places the disease locus in the Xp22.13-p22.11 region and excludes other X-linked disease loci causing retinal degeneration. The clinical expression of the retinal degeneration is consistent with X-linked dominant inheritance with milder, variable effects of Lyonization affecting expression in females. On the basis of these data we propose that this family has a novel form of dominant, X-linked cone-rod degeneration with the gene symbol "RP15."

The efficacies of four agents in ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 1600 mg/kg/injection sodium thiosulfate (STS), 300 mg/kg/injection diethyldithiocarbamate (DDTC), 18 mg/kg/injection WR-2721, or 300 mg/kg/injection fosfomycin (n = 10/group). Ototoxicity was assessed electrophysiologically by auditory brainstem responses (ABRs) and anatomically by cochlear histology. The greatest auditory protection was given by STS, followed by DDTC. WR-2721 and fosfomycin did not provide any protection. All of the animals in the STS and DDTC groups survived, while some fatalities occurred in the fosfomycin, WR-2721, and cisplatin-only groups. Thus, the agents that were protective against ototoxicity were also protective against mortality. The ABRs also provided evidence of cisplatin-induced neuropathy. In summary, STS and DDTC hold promise for ameliorating the ototoxic effects of cisplatin chemotherapy and the hamster proved to be an excellent model of cisplatin ototoxicity.

Platelet-activating factor (PAF) induces platelet aggregation and hypotension. It has been implicated in embryonic implantation, fetal lung maturation, and parturition. Alcohol abuse is associated with platelet dysfunction, chronic hypertension, and alcohol-related birth defects. We hypothesized that alcohol may cause, in part, these effects by increasing the activity of PAF-acetylhydrolase (PAF-AH), thereby decreasing PAF concentration. Pregnant mice were given 3.5 g/kg of alcohol orally twice daily from gestation days 7-17. PAF-AH was measured on gestation days 5, 14, and 19 in pregnant females. Nonpregnant females were treated and sampled at parallel time intervals. Pair-fed and untreated control groups were also used. The maternal plasma PAF-AH decreased with gestational age in the untreated controls. Alcohol significantly increased PAF-AH levels in both the pregnant and nonpregnant animals. PAF deficiency might contribute to the tocolytic action of alcohol, as well as some alcohol-related pregnancy complications.

Young adult hamsters were evaluated for normal variations in the auditory brain stem response (ABR) and for the effects of hearing loss. Normal variations in the ABR's latencies and amplitudes were defined for both click and tone burst stimuli over a broad range of intensities. As stimulus intensity decreased from 100 to 15 dB pe SPL, the ABR latencies were prolonged, the P4-P1 interpeak latencies varied in a complex manner, and amplitudes decreased. As tone burst frequency decreased from 8000 to 4000 and then to 2000 Hz, ABR latencies were prolonged, amplitudes decreased, and thresholds increased. The P4-P1 interpeak latencies were also influenced by tone burst frequency, with the longest interpeak latencies occurring in response to the 2000 Hz tone bursts. Data from two hamsters with hearing loss were compared to the normal data to illustrate how the ABR can be used to describe experimentally induced hearing impairment. Hearing impairment was induced by rearing animals in ambient noise. These animals showed elevated ABR thresholds at all three frequencies and upward displacements in the ABR's latency-intensity profiles.

Female rats prenatally exposed to alcohol were tested at 35 days of age for susceptibility to pentylenetetrazol (PTZ)-induced convulsions. There was a significant dose-response effect of PTZ. Contrary to expectations, alcohol-exposed females were slightly but still significantly less convulsion-prone than pair-fed controls. These results suggest prenatal alcohol exposure reduces the susceptibility to convulsions in rats.

Pregnant mice were given 50 mg/kg cocaine HCl (1% solution, sc) once daily from gestation days 7 through 18 (sperm positive = day 0; term = day 19). Pair-fed and untreated control groups were also used. The pregnant cocaine-treated females showed normal weight gain and food consumption but had significantly increased water consumption. The cocaine-treated group had a significant increase in embryonic resorptions but no significant effects on stillbirths or postnatal mortality. The offspring of cocaine-treated females had significantly reduced birth weights and postnatal weight gains up to the age of 28 days. There was also a delay in their ear opening but not in other maturational milestones. Increased water consumption following cocaine treatment has been reported by other studies. We speculate that cocaine has a diuretic effect. We discuss the implications of this effect during pregnancy.

Prenatal cocaine and alcohol exposures have been associated with a variety of adverse effects ranging from subtle neurobehavioral abnormalities to major malformations. In this study, we used the Porsolt swim test to assess the effects of prenatal cocaine and alcohol exposures on stress-related behavior. Pregnant Long-Evans rats were injected daily with 80 mg/kg cocaine HCl (SC) or 6.2-6.5 g/kg ethyl alcohol (PO) from gestation days 7-20 with half the dose given in the morning and the other half in the afternoon. Pair-fed and ad lib control groups were also used. One male offspring from each litter was evaluated in the Porsolt swim test at the age of 120 days. The alcohol and cocaine groups were less immobile (i.e., struggled more to escape) than the controls. These results suggest that prenatal exposure to either alcohol or cocaine can adversely affect behavior in stressful or fearful situations.

Rats prenatally exposed to alcohol (0%, 17.5%, or 35% ethanol-derived calories) were tested for audiogenic seizure susceptibility on one of postnatal days 18 to 23, then retested 5 days later. Prenatal alcohol exposure did not influence audiogenic seizure susceptibility or severity. There was, however, a significant increase in seizure incidence on the retest day for all groups, suggesting a priming effect. Auditory brainstem response (ABR) data suggested that prenatal alcohol exposure and acoustic trauma (i.e., exposure to an alarm bell used for eliciting audiogenic seizures) induced measurable sensorineural hearing loss, and that the combined exposure to alcohol and acoustic trauma interacted additively to produce greater hearing loss than either alone.

Young adult male Sprague-Dawley (SD) and Long-Evans (LE) rats were evaluated using the auditory brainstem response (ABR). ABRs were evoked by stimuli with intensities ranging from 15 to 100 dB peSPL. Stimuli were tone bursts of 2000, 4000 and 8000 Hz. As stimulus intensity decreased from 100 to 15 dB, the ABR peak latencies prolonged, interpeak latencies (IPLs) shortened and amplitudes decreased. As stimulus frequency decreased from 8000 to 2000 Hz, ABR latencies prolonged, amplitudes decreased and ABR thresholds increased. The longest IPLs were in response to the 4000 Hz tone bursts. SD rats had ABRs with shorter peak latencies, larger amplitudes and lower thresholds than LE rats. The IPLs usually did not show significant strain-dependent differences. Our observations on stimulus intensity and frequency are consistent with previous reports. Our observations also suggest that the SD (albino) rat has better auditory acuity than the LE (pigmented) rat over the frequency range of 2000 to 8000 Hz. This implies that previous concerns about the use of albino animals in audiological research are somewhat overstated.

Polydrug abuse has increased substantially in recent years amongst obstetric patients. One of the most common drug combinations is alcohol and cocaine. To better understand the adverse consequences of this drug combination on pregnancy and the offspring, alcohol (2 g/kg, b.i.d.) and cocaine HCl (30 mg/kg, b.i.d.) were administered individually and in combination to separate groups of pregnant Long-Evans rats from gestation days 7-20. The pregnant dams were evaluated for maternal weight gain, food and water consumption, mortality, and gestational length. The offspring were evaluated for physical maturation, mortality, and behavior. The drug combination was found to have greater effects regarding decreased birth weight, increased postnatal mortality, and delayed physical maturation than either drug alone. Drug treatments also influenced activity monitor behavior in that prenatal cocaine exposure was associated with hypoactivity while the alcohol and the alcohol-plus-cocaine treatments were associated with hyperactivity in periweanling pups. Drug treatments had no significant effects on passive or active avoidance behaviors. These results suggest that combining alcohol and cocaine increases the risk to the offspring.

Prenatal cocaine exposure has been associated with a variety of adverse neurological effects. Three recent studies found evidence that prenatal cocaine exposure is associated with abnormal auditory electrophysiology, suggesting abnormal processing of auditory information. The present study used the auditory brainstem response to evaluate the effects of prenatal cocaine exposure on hearing in an animal model (Long-Evans rat). We report that prenatal cocaine exposure can cause elevated ABR thresholds and latency-intensity curves consistent with a recruitment-type sensorineural hearing loss.

Prenatal exposure to cocaine has been shown to produce a variety of effects on skeletal development and mineralization in humans, mice, and rats. The effects of cocaine on bone cell function and mineral metabolism pre- and postnatally are poorly understood. The present study examined the long term effects of prenatal cocaine exposure on femoral growth and mineralization in male rats. Pregnant rats were given 80 or 100 mg cocaine hydrochloride/kg during days 7-20 of gestation. At birth, body weights of pups born to these females were significantly decreased compared to normal and pair-fed controls. At the termination of the study (32 weeks), body weights of offspring from C100-treated females were still lower than normal. Long term effects of prenatal exposure to cocaine on femoral growth were most pronounced in offspring of C80-treated females. Femur dry weight, ash weight, organic matrix weight and density were significantly reduced in these animals compared to normal or pair-fed controls. The apparent osteopenic effects of prenatal exposure to cocaine suggests some long term postnatal impact on bone cell or mineral metabolism. Previous studies of cocaine use during pregnancy in humans and animals have focused primarily on physical and behavioral defects in offspring. The present findings indicate that prenatal exposure to cocaine may also have long term consequences to the skeleton.

Pregnant Long-Evans rats were injected daily with 40, 60, 80 or 100 mg/kg cocaine HCl (SC, 2% solution) from gestational days 7-20 (sperm positive = day 0). Daily doses were split with half given between 9:00-10:00 a.m. and half between 3:00-4:00 p.m. An ad lib-fed group as well as nutritional control groups that were pair-fed to the 80 and 100 mg/kg cocaine dams were also evaluated (N = 11-18 litters/group). The negative geotactic reaction of the offspring, evaluated from day 2-14 (birth = day 0), showed no group differences. Spontaneous alternation behavior in a T-maze showed no evidence of perseveration in any group on either day 21 or day 80. Most cocaine-treated offspring showed an altered preference in turning right versus left on day 21. Activity monitor behavior showed that the cocaine-treated and pair-fed offspring were hypoactive on day 20. Some degree of hypoactivity was still evident on day 49, but absent on day 80. The passive avoidance behavior of day 19 offspring showed no group differences in acquisition of task learning. The 100 mg/kg cocaine offspring did show significantly poorer retention of task learning 48 hr later. On day 80, no group differences were seen in passive avoidance behavior. Acquisition of an active avoidance behavior on day 80 was significantly poorer in the 100 mg/kg cocaine group.

Prenatal cocaine exposure has been associated with a variety of adverse neurological effects in infants and laboratory animals. Of particular interest, one group of investigators reported that exposed neonates have an abnormality in the brainstem auditory-evoked potential (BAEP). The particular abnormality, a prolongation in the wave I-V interpeak latency, suggested delayed or desynchronized transmission of subcortical auditory information. To further investigate this possible consequence of prenatal cocaine exposure, pregnant Long-Evans rats were injected daily with 60, 80 or 100 mg/kg cocaine HCl (SC, 2% solution) with half the daily dose given in the morning and the other half given in the afternoon. Treatment was given from gestation days 7 to 20 (sperm positive = GD 0). Ad lib-fed and pair-fed control groups were also used. Offspring were evaluated at the age of 35 days (birth = PD 0) and as adults (6-10 months). BAEPs were elicited by click stimuli presented over a broad range of intensities and repetition rates. Prolongation of the interpeak latencies and a reduction in BAEP amplitudes were observed only in the highest dose (C100) group, only at the age of 35 days, and only at the highest stimulus intensity. While these results support those found in exposed neonates, our data suggest a) that the effects are developmental delays which dissipate with aging and b) that the effects require high cocaine exposure.

Pregnant Long-Evans rats were injected daily with 40, 60, 80, or 100 mg/kg cocaine HCl (SC, 2% solution) from gestational days 7-20 (sperm positive = day 0). Daily doses were split evenly with half given between 9:00-10:00 a.m. and half between 3:00-4:00 p.m. An ad lib-fed group as well as nutritional control groups that were pair-fed to the 80 and 100 mg/kg cocaine dams were also evaluated (N = 11-18 liters/group). Cocaine had no effect on gestational length but did cause dose-dependent decreases in maternal food consumption and weight gain and increases in maternal mortality. Interestingly, cocaine-treated dams shows a significant increase in water consumption. In terms of offspring variables, there was a dose-dependent decrease in birth weight and postnatal weight gain in both the cocaine and pair-fed groups. There were also dose-dependent effects on litter size, stillbirths and postnatal mortality in the cocaine-treated groups as compared to the control groups. High dose cocaine treatment caused delays in several indices of physical maturation (pinna detachment, fur growth, ear opening, eye opening, vaginal opening) but not in others (incisor eruption, testicular descent). Physical anomalies and postnatal morbidity, while uncommon, were observed in animals prenatally exposed to the higher cocaine doses. Collectively, these data suggest that prenatal cocaine exposure can increase postnatal morbidity as well as increase pre-and postnatal mortality in animal offspring.

Despite comparable alcohol consumption, not all women who drink excessively give birth to children with fetal alcohol effects or the fetal alcohol syndrome. Various maternal factors may be important in this regard. For example, two recent animal studies found that maternal age was an important risk factor in regard to alcohol's adverse effects on pregnancy. Specifically, alcohol produced greater maternal and fetal toxicity in older and middle-age mothers than in younger cohorts. An age-related difference in maternal blood alcohol concentrations (BACs), despite comparable alcohol administration, may have been the major factor. That is, older mothers may achieve higher BACs or take longer to eliminate alcohol from their blood, resulting in greater maternal and fetal toxicity. The present study was conducted to investigate this possibility. Dams were of three age groups: 2 1/4, 3 3/4 and 5 1/4 months old. Alcohol (3.5 g/kg p.o.) was administered twice daily at a 6-hr interval from gestation days 11 to 19. Blood samples were obtained on gestation day 19 at 1, 2, 4 and 6 hr after each injection. The data showed a progressive increase in peak BACs and a prolonged presence of alcohol with increasing maternal age. It was subsequently hypothesized that age-related differences in percent body water content might account for these effects, and we tested for this possibility. While age-related differences in body water content were found, administering alcohol doses on the basis of body water content did not equate BAC curves across the maternal age groups.(ABSTRACT TRUNCATED AT 250 WORDS)