Prenatal cocaine exposure disrupts the dopaminergic system and its postnatal responses to cocaine

Impaired attention is the hallmark consequence of prenatal cocaine exposure (PCE), affecting brain development, learning, memory and social adaptation starting at an early age. To date, little is known about the brain structures and neurochemical processes involved in this effect. Through focusing on the visual system and employing zebrafish as a model, we show that PCE reduces expression of dopamine receptor Drd1, with levels reduced in the optic tectum and other brain regions, but not the telencephalon. Organism‐wide, PCE results in a 1.7‐fold reduction in the expression of the dopamine transporter (dat), at baseline. Acute cocaine administration leads to a 2‐fold reduction in dat in drug‐naive larvae but not PCE fish. PCE sensitizes animals to an anxiogenic‐like behavioral effect of acute cocaine, bottom‐dwelling, while loss of DAT due to genetic knockout (DATKO) leads to bottom‐dwelling behavior at baseline. Neuronal calcium responses to visual stimuli in both PCE and DATKO fish show tolerance to acute cocaine in the principal regions of visual attention, the telencephalon and optic tectum. The zebrafish model can provide a sensitive assay by which to elucidate the molecular mechanisms and brain region‐specific consequences of PCE, and facilitate the search for effective therapeutic solutions.     

Prenatal exposure: The effects of prenatal cocaine and methamphetamine exposure on the developing child

Prenatal substance use remains a significant issue in the United States. Initial reports regarding prenatal cocaine and methamphetamine exposure suggested profound adverse effects on child development. However, subsequent prospective, longitudinal investigations have found more subtle effects. What follows is a brief review of the health, growth, behavioral, and intellectual outcomes for children exposed to prenatal cocaine and prenatal methamphetamine. Factors that may mitigate or intensify subtle adverse effects manifested in exposed children will also be discussed. Birth Defects Research (Part C) 108:142–146, 2016. © 2016 Wiley Periodicals, Inc.     

Effects of prenatal cocaine exposure in the photoreceptor cells of the rat retina

Despite the increasing evidence of eye abnormalities, the effects of prenatal exposure to cocaine on the visual system are still poorly understood. This study was aimed at analyzing the qualitative and quantitative organization of the retinal photoreceptor cells (PR) and outer nuclear layer (ONL) after prenatal exposure to cocaine in the rat. Pregnant Wistar rats were given sc injections of cocaine hydrochloride (60 mg/kg body wt/d) or saline or were not manipulated; analyses were performed in the 14- and 30-d-old male offspring. Radial semithin and ultrathin sections of epon-embedded flat mounts of the retina showed displaced PR-like cells in the inner nuclear layer (INL), picnotic PR nuclei in INL, and ONL, and retinal PR rosettes and outer-segment debris in the subretinal space. The quantitative study showed an increased density of PR-like nuclei in the INL in PND14 cocaine-treated rats that were within normal values at PND30; no changes were detected in the PR mean nuclear diameter and in the packing density of PR nuclei in the ONL. These data constitute the first morphological demonstration of photoreceptor damage after prenatal cocaine-exposure probably owing to a direct action of the drug and/or to the cocaine-induced ischemia/hypoxia.     

大鼠产前母体冷应激对子代自发、探索及焦虑行为的影响*

目的: 研究产前冷应激对妊娠大鼠子代行为及情绪的影响。方法: 将6只SPF级Wister妊娠母鼠,随机分为常温对照组和冷应激组,每组3只。常温对照组妊娠母鼠在(22±2)℃的环境中饲养,冷应激组妊娠母鼠在产前7 d置于人工智能气候室(4±0.1)℃中饲养,待产下幼鼠以后,分为常温对照组公鼠(MR,22只),常温对照组母鼠(FR,15只),冷应激组公鼠(MC,15只),冷应激组母鼠(FC,15只)四组,在子代第四周龄时进行旷场实验、高架十字迷宫实验。结果: 在旷场实验中,常温对照组公鼠、母鼠与冷应激组公鼠、母鼠的自发活动、探索行为之间无明显差异(P＞0.05)。在高架十字迷宫实验中,冷应激组公鼠、母鼠的开臂滞留时间、开臂进入次数及路程等总体上显著高于常温对照组公鼠、母鼠(P＜0.05)。结论: 产前母体冷应激对子代自发活动、探索行为及活跃程度无显著影响,但子代出现明显的焦虑行为减少的异常行为。     

Effects of In utero environment and maternal behavior on neuroendocrine and behavioral alterations in a mouse model of prenatal trauma

Maternal posttraumatic stress disorder (PTSD) following trauma exposure during pregnancy is associated with an increased risk of affective disorders in children. To investigate the mechanisms by which prenatal trauma and/or maternal PTSD affect brain development and behavior we established a mouse model of prenatal traumatic (PT) experience based on the application of an electric foot shock to C57Bl/6N female mice on the gestational day 12 during their pregnancy. The model is based on a previously validated animal model of PTSD. We found high anxiety levels and poor maternal care along with reduced serum prolactin and increased corticosterone levels in dams following maternal trauma (MT). PT‐pups were born smaller and stayed smaller throughout their life. We show increased time and frequency of ultrasonic calls in PT‐pups when separated from the mothers on the postnatal day (PND) 9. Cross‐fostering experiments reveal lower anxiety levels in PT pups raised by healthy mothers as compared to trauma‐naive pups raised by MT‐dams. Importantly, the combination of prenatal trauma and being raised by a traumatized mother leads to: (1) the highest corticosterone levels in pups, (2) longest USV‐call time and (3) highest anxiety levels in comparison to other experimental groups. Our data indicates a distinct change in maternal care following MT which is possibly associated with trauma‐induced decrease in prolactin levels. Furthermore, we show that maternal behavior is crucial for the development of the offspring anxiety and specific aspects in maternal care overwrite to a significant extend the effects of in utero and postnatal environment. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1254–1265, 2016     

Influence of maternal stress on metal-induced pre- and postnatal effects in mammals

Studies in rodents have shown that, during pregnancy, maternal stress from restraint, noise, light, and heat among other factors may be associated with adverse effects on embryo/fetal and postnatal development. Moreover, it is also well known that exposure to certain metal levels during gestation can also cause maternal and developmental toxicity. Because potentially, pregnant women may be concurrently exposed to metals and various types of stress, the influence of maternal stress on the metal-induced adverse pre-and postnatal effects has been investigated for a number of elements. This influence is reviewed here. It is concluded that maternal stress enhances the metal-induced embryo/fetal and developmental toxicity only at doses of the metal which are also clearly toxic to the dam.     

Effects of prenatal cocaine, morphine, or both on postnatal opioid (mu) receptor development

We studied the effects of prenatal cocaine and morphine given separately and in combination on the (1) postnatal brain mu-opioid receptor development and (2) interaction of dopamine with mu receptors. Pregnant rats received single daily intraperitoneal (I.P.) injections of saline, cocaine (20 mg/kg), morphine (2 mg/kg), or the combination of both drugs from day 13 to day 20 of gestation. Postnatal days (P) 1, 7, 14, and 28, whole brains were analyzed for opioid receptor binding and mu mRNA. Prenatal cocaine administered by itself had no significant effect on the ontogeny of brain mu receptors on all the days studied when compared to controls. The morphine-treated group showed a significant increase in mu receptor binding on P1 and P7. Exposure to both cocaine and morphine showed a significant increase in mu receptor density on P1 and P7. In addition, there was also a significant increase in MOR mRNA in both the morphine alone and combination groups. Pretreatment with dopamine D2 receptor antagonist (sulpiride, 20 mg/kg) prior to drug administration showed decreased mu receptor binding on P1 and P7. These results suggest that prenatal exposure to morphine or a combination of cocaine and morphine significantly increases mu receptor density. By P14, mu-opioid receptor binding was no longer different than the control. This may suggest that the effect on receptor may be short-lived and that other key intracellular events may be activated to mediate the long-term effects. Also, the data show that dopaminergic mechanisms are (or opioid-dopamine interaction is) involved in the effects of morphine alone or morphine in combination with cocaine on mu receptor regulation.     

Lack of adverse effects in pregnant/lactating female rats and their offspring following pre- and postnatal exposure to ELF magnetic fields

We have recently reported that exposure of pregnant rats to 60 Hz at field strengths up to 0.5 mT during the entire period of pregnancy did not induce any biologically significant effects on both pregnant dams and embryo-fetal development. The present study was carried out to investigate the potential effects of gestational and lactational MF exposure on pregnancy, delivery, and lactation of dams and growth, behavior, and mating performance of their offspring in rats. Timed-pregnant female Sprague-Dawley (SD) rats (24/group) received continuous exposure to 60 Hz magnetic field (MF) at field strengths of 0 (sham control), 5 microT, 83.3 microT, or 0.5 mT. Dams received MF or sham exposures for 21 h/day from gestational day 6 through lactational day 21. Experimentally generated MF was monitored continuously throughout the study. No exposure-related changes in clinical signs, body weight, food consumption, pregnancy length, and necropsy findings were observed in dams. Parameters of growth, behavior, and reproductive performance of offspring showed no changes related to MF exposure. There were no adverse effects on embryo-fetal development of F2 offspring from dams exposed to MF. In conclusion, exposure of pregnant SD rats to 60 Hz at field strengths up to 0.5 mT from gestational day 6 to lactational day 21 did not produce biologically significant effects in dams, F1 offspring, or F2 fetuses.     

妊娠期给予可卡因对母体和胎儿的影响: 小鼠动物模型

探讨妊娠期给予可卡因对母体和胎儿的影响。妊娠小鼠分为3组：可卡因注射组（每日两次注射盐酸可卡因10mg/kg,COC);盐水对照组（每日两次注射生理盐水10ml/kg,SAL);饮食对照组（每日两次注射生理盐水10ml/kg,饮食参考可卡因给药组,SPF）。用高压液相色谱分析法检测胎鼠血中可卡因浓度及纹状体中神经递质多巴胺和5－羟色胺的含量,并结合HE染色观察胎鼠肝脏和胎盘的形态学改变。尽管COC和SPF组母鼠摄食量和体重增长量均降低,但是仅仅COC组胎鼠的体重和脑重减少。高压液相色谱分析结果显示,在COC组胎鼠血浆中可检测出可卡因,并伴有纹状体神经递质含量的异常增高。同时,也观察到了COC组胎盘和肝脏的形态学变化。本研究表明,妊娠期给予可卡因能引起妊娠母体营养不良,子代脑、肝脏和胎盘发育异常;可卡因引起的胎儿发育异常是由可卡因的毒性作用而不是母体营养不良产生的。     

MPOA cytotoxic lesions and maternal behavior in the rat: effects of midpubertal lesions on maternal behavior and the role of ovarian hormones in maturation of MPOA control of maternal behavior

Small neurotoxin lesions in the medial preoptic area (MPOA) block maternal behavior (MB) in adults but large lesions are required to produce the same effect in juvenile rats (23-27 days of age). To study the maturation of MPOA control of MB, in Experiment I, we compared the effects of small versus large neurotoxin MPOA lesions at midpuberty (38 days of age) on MB. Midpubertal females with large MPOA lesions showed severe impairment in MB affecting retrieving, crouching, and nest building, but 85% of females with small MPOA lesions exhibited all components of MB and performed like control females without MPOA lesions. To study the role of ovarian hormones during puberty on the maturation of MPOA mediation of MB (Experiment IIA), females were ovariectomized either before or after puberty and small MPOA cytotoxic lesions were made at 53 days of age. At 60 days of age both groups showed similar deficits in MB which indicated that the maturation of the MPOA mediation of MB is not dependent on pubertal ovarian hormones. In Experiment IIB, we administered estradiol benzoate (sc) and this overcame the deficit in MB after small MPOA lesions in females that had been deprived of estrogen for shorter periods (30 days) but had not been deprived for longer periods (60 days). In addition, ovary-intact females with circulating estrogen and small lesions in the MPOA at 53 days of age did not show deficits in MB.     

Long-term effects of prenatal stress on dopamine and glutamate receptors in adult rat brain

Prenatal stress greatly influences the ability of an individual to manage stressful events in adulthood. Such vulnerability may result from abnormalities in the development and integration of forebrain dopaminergic and glutamatergic projections during the prenatal period. In this study, we assessed the effects of prenatal stress on the expression of selective dopamine and glutamate receptor subtypes in the adult offsprings of rats subjected to repeated restraint stress during the last week of pregnancy. Dopamine D₂-like receptors increased in dorsal frontal cortex (DFC), medial prefrontal cortex (MPC), hippocampal CA₁ region and core region of nucleus accumbens (NAc) of prenatally stressed rats compared to control subjects. Glutamate NMDA receptors increased in MPC, DFC, hippocampal CA₁, medial caudate-putamen, as well as in shell and core regions of NAc. Group III metabotropic glutamate receptors increased in MPC and DFC of prenatally stressed rats, but remained unchanged in all other regions examined. These results indicate that stress suffered during the gestational period has long lasting effects that extend into the adulthood of prenatally stressed offsprings. Changes in dopamine and glutamate receptor subtype levels in different forebrain regions of adult rats suggest that the development and formation of the corticostriatal and corticolimbic pathways may be permanently altered as a result of stress suffered prenatally. Maldevelopment of these pathways may provide a neurobiological substrate for the development of schizophrenia and other idiopathic psychotic disorders.     

Effect of prenatal and postnatal ethanol exposure on the developmental profile of mRNAs encoding NMDA receptor subunits in rat hippocampus

It has been proposed that assembly of the final NMDA receptor complex may be modified by prenatal ethanol exposure, resulting in long-term alterations of NMDA receptor pharmacology. We investigated the effect of prenatal and postnatal ethanol exposure on the developmental profile of mRNAs encoding NMDA receptor subunits in rat hippocampus. Female Sprague-Dawley rats were chronically intoxicated for 4 weeks with a 10% (v/v) ethanol solution administered throughout pregnancy and lactation. Hippocampus and cerebellum were isolated from pups (postnatal days 1-28) of the ethanol-exposed and ad libitum groups. Our results, using a semiquantitative RT-PCR technique, showed a selective effect of ethanol exposure on the various NMDA receptor subunits. Ethanol exposure significantly increased the levels of NR1(1XX), NR1(X11) and NR2(D) mRNAs on postnatal days 7 and 14 and decreased the level of NR2(C) on postnatal day 1. Immunoblot analyses demonstrated that NR2(D) protein levels were increased on postnatal day 7 after ethanol exposure. However, the developmental profile of mRNAs encoding for NR2(A-B), NR3(L/S), GBP and Gly/TCP-BP subunits were not affected. Moreover, no significant effects of ethanol exposure were observed on the developmental transition from expression of NR1(0XX) to NR(1XX) splice variants occurring in the cerebellum on postnatal day 19. Unexpectedly, [(3) H]MK-801 binding experiments showed that ethanol exposure increased the B (max) values of high-affinity sites on postnatal days 14 and 28, with no change of K (d) values. These findings indicate that prenatal and/or postnatal ethanol exposure alters the hippocampal levels of mRNAs encoding for certain subunits and the density of high-affinity [(3) H]MK-801 binding sites. As these subunits have been shown to modulate the functional properties of NMDA receptors, these results suggest that this altered expression could be involved in the neurodevelopmental disorders associated with fetal ethanol exposure.     

The effects of adrenalectomy and corticosterone replacement on induction of maternal behavior in the virgin female rat

Maternal behavior of the sensitized virgin rat is affected by approach-avoidance systems as well as by hypothalamic-pituitary-adrenal (HPA) axis, which is also activated during stress. The present experiments investigated the effects of adrenalectomy and of varying corticosterone concentrations on the onset and expression of maternal behavior in sensitized virgin rats. In the first experiment, latency to onset of maternal behavior and time spent licking once maternal were positively related to endogenous levels of corticosterone. However, few rats showed licking. In the second experiment, virgin rats were adrenalectomized or given sham surgeries before being sensitized and being given 0, 25, 100, 300, or 500 microg/mL of corticosterone in their drinking water. In the third experiment, virgin rats were adrenalectomized or given sham surgeries and given either control or corticosterone time-release pellets after being sensitized. Maternal behavior was then tested. Adrenalectomy increased licking in the second experiment and time over pups in the third experiment. Corticosterone replacement reduced licking in the second experiment and both licking and time over pups in the third experiment. In conclusion, exogenous corticosterone had an inhibitory effect on the expression of maternal behavior in the sensitized virgin rat, unlike the facilitatory effect previously found in the postpartum rat.     

Prenatal cocaine exposure revealed minimal postnatal changes in rat striatal dopamine D2 receptor sites and mRNA levels in the offspring

It has been reported from this laboratory that prenatal cocaine exposure results in the postnatal transient alterations of rat striatal dopamine uptake sites examined from postnatal 0–32 wk. The present study aims to examine whether this will result in a direct/indirect stimulation of dopamine D₂ receptors. Pregnant rats were dosed orally with cocaine hydrochloride (60 mg/kg/d) from gestational day (GD) 7–21. Control animals received an equivalent volume of water. The striatum from the offspring at postnatal 0–32 wk was examined. The radioligand [³H]sulpiride was used for the Scatchard analysis of the D₂ receptors, and the changes in the levels of mRNA for the D₂ receptor were studied using Northern blot analysis. Results from the present study revealed that in the control group, there was an age-dependent increase in the number of D₂ receptor sites (B _max:44.00±2.12 to 178.00±45.10 fmol/mg protein) and in the levels of D₂ mRNA from PN0–32 wk with the most rapid increase occurring during the first 4 wk of postnatal development. Prenatal cocaine exposure resulted in only a significant decrease (p<0.001) in the number of D₂ receptor sites at PN0 wk and in a 10% increase in mRNA levels at PN3, 4, and 12 wk. It was concluded from this study that prenatal cocaine exposure resulted in minimal postnatal changes in the dopamine D₂ receptor.     

Cardamom (Elettaria cardamomum) perinatal exposure effects on the development,behavior and biochemical parameters in mice offspring

Cardamom is a strong antioxidant plant, so it is called the queen of spices. In the present study, we explored the potentials of cardamom on developmental, learning ability and biochemical parameters of mice offspring. Thirty pregnant mice were allocated to three groups of ten animals in each. Groups Π and Ш received pilsbury's Diet containing 10 and 20% of cardamom (w/w) respectively, whereas Group I used as control. Cardomom was administered from the first day of pregnancy and was continued until post-natal day 15 (PD 15) and thereafter the mothers were switched to plain pilsbury's Diet. During the weaning period, three pups in each litter were color marked from the others, and were subjected to various tests (Physical assessment such body weight and eye opening and hair appearance; the neuromaturation of reflexes like righting, rotating, and cliff avoidance reflexes; learning ability and memory retention; estimation of monoamines neurotransmitters like dopamine and serotonin, non-enzymatic oxidative stress such as TBARS and GSH in forebrain at different ages of pups). The results indicated that the body weight gain was declining significantly. Hair appearance and eyes opening were delayed significantly. Righting, rotating, and cliff avoidance reflexes were delayed in treated animals. Exposure to cardamom led to enhance learning and memory retention as compared to control. Monoamines (DA, 5-HT) and GSH were elevated, whereas TBARS was inhibited significantly. In conclusion, perinatal cardamom exposure enhanced learning and memory as compared to control. Cardamom and its benefit compounds were transported via placenta or/and milk during lactation. Cardamom needs more researches to investigate its benefits on other kinds of behavior.     

产前850-1900MHz手机暴露对子代大鼠齿状回PCNA和DCX表达的影响

目的：探讨产前手机暴露对子代大鼠海马齿状回增殖细胞核抗原（PCNA）和双皮质素（DCX）表达的影响。方法：构建孕鼠手机射频暴露模型,分为对照组、短时暴露组和长时暴露组（n=6）,短时和长时暴露组于孕第1-17天分别给予6 h/d和24 h/d的手机通话暴露,观察孕鼠的孕期长短、孕期体重增长和各组的胎儿数、胎儿出生体重。1月龄子代大鼠行焦油紫染色观察海马齿状回细胞形态,免疫组化观察齿状回PCNA和DCX表达,Western blot检测DCX和脑源性神经营养因子（BDNF）表达。结果：各组孕鼠的孕期、妊娠期体重增长和各组的胎儿数、胎儿出生体重无显著差异,长时暴露组子代大鼠的齿状回多形细胞层锥形细胞和DCX阳性细胞出现形态改变。与对照组、短时暴露组比较,长时暴露组子代大鼠齿状回PCNA阳性细胞和DCX、BDNF表达均明显减少（P<0.05）。结论：产前长时手机暴露可能通过改变子代大鼠海马BDNF而影响齿状回的PCNA和DCX表达。     

The effects of adrenalectomy and corticosterone replacement on maternal behavior in the postpartum rat

It is well known that the hypothalamic-pituitary-adrenal (HPA) axis is activated during stress. Recent work suggests it is also implicated in the regulation of "normal" behaviors. The present studies investigated the effects of adrenalectomy and of varying glucocorticoid concentrations on adult maternal behavior in primiparous rats. In two studies, rats in late pregnancy were adrenalectomized or given sham surgeries and were tested for maternal behavior. In the first study, primiparous rats were given 0, 25, 100, 300, or 500 microg/ml of corticosterone in their drinking water. In the second study, primiparous rats were given either control or corticosterone time-release pellets. Blood samples were taken to ensure that rats demonstrated levels of corticosterone in blood that were relative to doses received. In studies one and two, primiparous adrenalectomized rats showed slightly, but significantly, lower levels of some maternal behaviors, including licking and time in nest, than primiparous sham rats. Primiparous rats given higher doses of corticosterone replacement showed higher levels of these maternal behaviors than primiparous rats given lower doses of corticosterone. In conclusion, adrenalectomy decreases, but does not abolish, maternal behavior. Corticosterone replacement reverses these effects. Corticosterone is not necessary for the initiation or maintenance of maternal behavior but plays a role in the modulation of ongoing maternal behavior.     

Reproductive and neurobehavioral effects of maternal exposure to piperonyl butoxide (PBO) in F1‐generation mice

Female mice were exposed maternally to piperonyl butoxide (PBO) through diet to provide levels of 0 (control), 0.015, 0.03, and 0.06% during gestation and lactation periods, and selected reproductive and neurobehavioral parameters were measured in F₁ generation. There was no adverse effect of PBO on litter size, litter weight, or sex ratio at birth. The average body weights of offspring showed no significant effects of PBO treatment through the lactation period in both sexes except for the low‐dose group of females on PND 21. With respect to behavioral developmental parameters, swimming direction of female offspring on PND 7 was significantly accelerated in the low‐dose group (p = 0.022). Exploratory behavior examination in male offspring indicated that total distance and movement time shortened significantly in dose‐related manners (p = 0.0138 and 0.00231, respectively), average time of rearing lengthened significantly in a dose‐related manner (p = 0.00814), and the frequencies of mice with urination was increased significantly in a dose‐related manner (p < 0.05). For spontaneous behavior examination, the average time of movement in males and average time of rearing in females showed slightly dose‐related effects in the F₁ generation. The dose levels of PBO in the present study produced some adverse effects in neurobehavioral parameters in mice.     

Simulation analysis to test the influence of model adequacy and data structure on the estimation of genetic parameters for traits with direct and maternal effects

Simulations were used to study the influence of model adequacy and data structure on the estimation of genetic parameters for traits governed by direct and maternal effects. To test model adequacy, several data sets were simulated according to different underlying genetic assumptions and analysed by comparing the correct and incorrect models. Results showed that omission of one of the random effects leads to an incorrect decomposition of the other components. If maternal genetic effects exist but are neglected, direct heritability is overestimated, and sometimes more than double. The bias depends on the value of the genetic correlation between direct and maternal effects. To study the influence of data structure on the estimation of genetic parameters, several populations were simulated, with different degrees of known paternity and different levels of genetic connectedness between flocks. Results showed that the lack of connectedness affects estimates when flocks have different genetic means because no distinction can be made between genetic and environmental differences between flocks. In this case, direct and maternal heritabilities are under-estimated, whereas maternal environmental effects are overestimated. The insufficiency of pedigree leads to biased estimates of genetic parameters.     

The effects of manganese deficiency during prenatal and postnatal development on mitochondrial structure and function in the rat

The influence of manganese deficiency on liver trace element concentration, MnSOD activity, and mitochondrial structure and function during postnatal development was determined in rats. In both normal and manganese-deficient animals, liver manganese concentration increased with time, but in deficient rats liver manganese was lower than in controls at all ages measured. At 9 mo of age, liver manganese concentration in the deficient rats was only 20% that of controls. The developmental pattern observed for MnSOD paralleled that of liver manganese concentration in normal and deficient rats; it was lower than in controls on days 20 and 60. However, at 9 mo of age, MnSOD levels were similar in the two groups. Although there were no differences at 9 mo of age in MnSOD activity between the groups, manganese-deficient rats showed mitochondrial abnormalities in liver. Despite mitochondrial abnormalities, however, oxygen uptake and P/O ratios were normal. We suggest that the mitochondrial damage apparent at 9 mo of age is, at least in part, the result of lower than normal MnSOD activity occurring earlier. The functional significance of the abnormalities remains to be established.