Dietary LC-PUFA in iron-deficient anaemic pregnant and lactating guinea pigs induce minor defects in the offsprings' auditory brainstem responses.

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.

Mild iron deficiency anaemia during pregnancy and lactation in guinea pigs alters amplitudes and auditory nerve velocity, but not brainstem transmission times in the offspring's auditory brainstem response.

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' enhances noise-induced hearing loss.

'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.

The effects of aggressive vs. conservative phototherapy on the brainstem auditory evoked responses of extremely-low-birth-weight infants.

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.

Auditory brainstem response (ABR) abnormalities across the life span of rats prenatally exposed to alcohol.

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.

Mild maternal iron deficiency anemia during pregnancy and lactation in guinea pigs causes abnormal auditory function in the offspring.

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.

Repeated courses of antenatal corticosteroids: are there effects on the infant's auditory brainstem responses?

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.

Perinatal n-3 fatty acid imbalance affects fatty acid composition in rat offspring.

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.

Auditory brainstem response abnormalities and hearing loss in children with craniosynostosis.

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.

Reduced auditory acuity in rat pups from excess and deficient omega-3 fatty acid consumption by the mother.

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.

Fatty acid ethyl esters in meconium: are they biomarkers of fetal alcohol exposure and effect?

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.

WR-2721 (Amifostine) ameliorates cisplatin-induced hearing loss but causes neurotoxicity in hamsters: dose-dependent effects.

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.

Prenatal cocaine exposure influences the growth and life span of laboratory rats.

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.

Effects of Prenatal Cocaine on Hearing, Vision, Growth, and Behaviora.

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.