Genetic and ethanol-related differences in maternal behavior and offspring viability in mice

Primiparous female mice of 2 lines genetically selected for different narcotic responses to ethanol were administered 10% (v/v) ethanol in their drinking water during Days 2-14 of lactation. Ethanol treatment resulted in a marked decrease in growth and viability of pups in both lines. Fewer offspring of the ethanol-sensitive line survived to weaning, apparently because of the failure of a large number of dams to exhibit maternal care. The combination of ethanol treatment and an additional environment stressor (mouse hepatic virus) had a devastating effect on maternal behavior and offspring survival in the ethanol-sensitive line, but far less effect on the ethanol-insensitive mice. Thus, ethanol-sensitive animals appear to be more susceptible to a variety of stressors, including ethanol.     

Alterations in behavior in adult offspring mice following maternal inflammation during pregnancy

Maternal intrauterine inflammation during pregnancy poses a major threat of neurodevelopmental brain damage in offspring and may cause poor cognitive and perceptual outcomes. In mice, we have previously shown that maternal inflammation induced by lipopolysaccharide (LPS) at gestation day 17th increased the levels of the pro-inflammatory cytokine IL-6 in the fetal brain. In this study, we used the same system and examined the effect of short, systemic maternal inflammation on anxiety and social behavior of the offspring. Adult offspring from the maternal inflammation group showed increased anxiety, as indicated by the elevated plus maze. Social interaction among offspring from the test groups was examined when two unfamiliar mice from different litters were introduced into a new home-cage. Offspring from the maternal inflammation group showed reduced activity, indicating increased fear. In addition, offspring from the maternal inflammation group were less aggressive towards their cagemates and they spent a significantly longer time trimming the whiskers of their cagemates during the first 30 min of their interaction, compared to offspring from the control group. Our data suggest that short systemic maternal inflammation have long-lasting consequences on the adult mouse stress and social behavior.     

Maternal care affects the development of maternal behavior in inbred mice

The present study investigated the effects of variations in maternal behavior on the development of maternal behavior of female offspring in BALB/c and CBA/Ca inbred mice. In Experiment 1, we conducted fostering within or between the two strains and observed the maternal behaviors of mothers and female offspring for 2 weeks postpartum. Although fostering changed the maternal behavior of mothers in both strains, CBA mothers generally showed greater frequency of nursing posture and pup licking than BALB mothers. BALB female offspring reared by CBA mothers showed more body licking than those reared by BALB mothers, whereas fostering did not affect the maternal behavior of CBA female offspring. In Experiment 2, we examined the maternal behavior of females of F1 hybrids derived from reciprocal crosses between the two strains to confirm the maternal effect demonstrated in Experiment 1. Female F1 hybrids from CBA mothers showed more arched‐back nursing, body licking, and nest building than those from BALB mothers. These results suggested that maternal care affect the development of maternal behavior in inbred mice, though the contributions of genetic and prenatal factors cannot be ignored. © 2009 Wiley Periodicals, Inc. Dev. Psychobiol 51: 345–357, 2009.     

1,2-Dimethylhydrazine carcinogenesis in CBA male mice prenatally treated with diethylstilbestrol.

CBA female mice, at the 17th day of pregnancy, received single intraperitoneal injection of diethylstilbestrol (DES) at the dose of 1 mg/kg body weight (b. w.). Their descentands at the age of 2 months started receiving subcutaneous injections of 1,2-dimethylhydrazine (DMH) at the dose level of 8 mg(base)/kg b. w., total 15 weekly injections. Prenatal DES treatment of male mice considerably accelerated the development and increased the incidence of DMH-induced androgen-dependent renal adenomas and, notably, renal capsule angiosarcomas (RCA). In males receiving prenatal DES (without subsequent DMH-treatment), there was a statistically significant increase of renal adenomas and 9% of RCA were observed which are exceedinly rare in untreated mice. The enhancement of androgen-dependent tumourigenesis may be considered as an indication, even though indirect, of the hyperandrogenization produced in male mice by the prenatal DES treatment.     

Maternal separation alters maternal care, but has minor effects on behavior and brain opioid peptides in adult offspring

The aim of the study was to investigate the effect of repeated maternal separation (MS; 4 hr per day) during postnatal Days 1 to 15 on emotionality and voluntary ethanol intake in adult male and female Wistar rat offspring relative to controls exposed to a brief (5-min) daily handling procedure. Brain immunoreactive opioid peptide levels and plasma levels of corticosterone also were measured. There were mainly no alterations in any of the tested behaviors (i.e., fleeing and freezing responses, exploratory behavior, spontaneous and amphetamine-induced locomotor activity and competitive behavior), ethanol intake, or immunoreactive opioid peptide levels in MS offspring, either in males or females, compared to their respective controls nor were there any differences in plasma corticosterone between groups. In addition, the dams' retrieval behavior of the pups also was studied, showing that MS dams spent more time in the nest with the pups after the 4-hr separation period compared to control dams. With respect to the used protocol of the MS procedure in the present study, our results do not provide support for the suggestion that this procedure is a relevant model for studying development of psychopathology and vulnerability to drug abuse.     

Fertility and offspring survival in mice selected for different sensitivities to alcohol

The LS (long-sleep) and SS (short-sleep) selected lines of mice exhibit relatively high and low sensitivity to alcohol, respectively, because of their previous history of selective breeding. The present study identifies other differences between the two lines. SS animals are almost twice as fertile as LS animals. Analysis of vaginal plug formation suggested that higher sexual activity of SS mice is an important component of their greater fertility. Forced maternal drinking of a 10% ethanol solution during gestation, and especially during lactation, caused a decrease in survival of LS but not of SS offspring. Increased cannibalism of pups by LS mothers was probably an important component of this decrease in progeny survival. Maternal consumption of liquid in both lines was decreased during gestation, and especially during lactation, when 10% ethanol was the only available liquid in each case. The physiological basis for decreased survival of LS progeny may involve either direct effects of alcohol on progeny or indirect effects caused by water, nutritional, or hormonal imbalance in LS mothers when they are exposed to alcohol stress. The relationship of fertility and progeny survival differences in the two lines to their differences in alcohol sensitivity produced by selective breeding is discussed.This research is part of a thesis submitted by Darius S. Baer as partial fulfillment of the requirements for the M.A. degree in the Department of Environmental, Population, and Organismic Biology at the University of Colorado. It was supported in part by NIMH Training Grant MH-11167 and NIAAA Research Grant AA-00293 to Dr. Gerald E. McClearn of the Institute for Behavioral Genetics at the University of Colorado.     

Alternations in the maternal behavior of rats rearing malnourished offspring

Investigations of maternal behavior of mothers fed a low-protein diet indicated deficits in retrieval and in the rate of nest-building. In addition, they indicated a concomitant increase in time spent with young when assessed during periods not associated with the retrieval/nest-building test session. The adrenalectomized mother, another case that produces growth-stunted progeny, was compared with both low-protein and control mothers for maternal behavior. Unlike the low-protein mother, the adrenalectomized mother did not exhibit retrieval or nest-building deficits; however, the adrenalectomized mother did display an increase in time spent with young. These data suggest that although deficits in retrieval and nest-building can be attributed to the nutritional condition of the mother, the stimulus characteristics of the malnourished pup are important in eliciting the increased time spent with the litter.     

Molecular and organismal changes in offspring of male mice treated with chemical stressors

Both gene methylation changes and genetic instability have been noted in offspring of male rodents exposed to radiation or chemicals, but few specific gene targets have been established. Previously, we identified the gene for ribosomal RNA, rDNA, as showing methylation change in sperm of mice treated with the preconceptional carcinogen, chromium(III) chloride. rDNA is a critical cell growth regulator. Here, we investigated the effects of paternal treatments on rDNA in offspring tissue. A total of 93 litters and 758 offspring were obtained, permitting rigorous mixed‐effects models statistical analysis of the results. We show that the offspring of male mice treated with Cr(III) presented increased methylation in a promoter sequence of the rDNA gene, specifically in lung. Furthermore polymorphic variants of the multi‐copy rDNA genes displayed altered frequencies indicative of structural changes, as a function of both tissue type and paternal treatments. Organismal effects also occurred: some groups of offspring of male mice treated with either Cr(III) or its vehicle, acidic saline, compared with those of untreated mice, had altered average body and liver weights and levels of serum glucose and leptin. Males treated directly with Cr(III) or acidic saline presented serum hormone changes consistent with a stress response. These results establish for the first time epigenetic and genetic instability effects in a gene of central physiological importance, in offspring of male mice exposed preconceptionally to chemicals, possibly related to a stress response in these males. © 2012 Wiley Periodicals, Inc.     

Alterations in the maternal behavior of rats rearing hypothyroid and hyperthyroid offspring

To determine whether maternal behavior could serve as a mediator for thyroid hormone effects on behavior, I assessed nesting, nursing, grooming, contact, and retrieval in mothers of hypothyroid, hyperthyroid, and control litters, as well as in mothers of litters receiving thyroxine replacement therapy. Females assigned to the hypothyroid and replacement therapy treatments were placed on a goitrogenic diet of 2% propylthiouracil from Day 15 of gestation to Day 22 postpartum. Hyperthyroid and replacement therapy pups were injected daily with thyroxine starting on the day of birth. The decline in nesting and nursing was delayed in hypothyroid litters whereas the decline in nesting was accelerated in hyperthyroid litters. Retrieval was not affected, but grooming of pups occurred less frequently in hypothyroid and replacement therapy litters. Maternal care received by hypothyroid pups was considered adequate. Maternal behavior may alleviate some of the effects of perinatal hypothyroidism, but does not seem to be responsible for the more severe effects of hypothyroidism.     

Overlapping litters in rats: effects on maternal behavior and offspring emotionality

Female rats have a fertile postpartum estrus, which can result in a simultaneous gestation and lactation and later in the overlapping of two different-age litters. These different physiological and contextual situations may affect the maternal behavior of lactating rats and provoke long-lasting changes in the affective behavior of the litter. Therefore, we aimed to assess the effect of pregnancy and of litter overlapping on the maternal behavior of lactating rats and to describe the maternal- and anxiety-like behaviors of the juveniles that remained in contact with their younger siblings. Results showed that pregnant lactating rats spent more time outside the nest and less time nursing than non-pregnant mothers. On the other side, mothers with overlapping litters licked less the newborn pups than mothers with single litters. These deficits in maternal licking received by neonates were overridden by the juveniles' licking behavior to their younger siblings. Adult male and diestrous female rats reared with younger siblings showed a reduced anxiety-like behavior as compared to age-weaning matched animals without this experience. Thus, natural changes in the reproductive conditions and in the early experience, affect the maternal behavior and long-term modulate affective behavior of the individuals.     

Multi-dimensional analyses of behavior in mice treated with naltrexone

The effects of naltrexone on the behavior in mice were investigated by using a multi-dimensional behavioral analyser. Within 15 min following observation, naltrexone preferentially suppressed the linear locomotion at the 10 and 30 mg/kg doses. The results suggest that naltrexone selectively disrupts the linear locomotion without affecting other behaviors in mice.     

Prenatal environmental tobacco smoke exposure increases allergic asthma risk with methylation changes in mice

Allergic asthma remains an inadequately understood disease. In utero exposure to environmental tobacco smoke (ETS) has been identified as an environmental exposure that can increase an individual's asthma risk. To improve our understanding of asthma onset and development, we examined the effect of in utero ETS exposure on allergic disease susceptibility in an asthmatic phenotype using a house dust mite (HDM) allergen‐induced murine model. Pregnant C57BL/6 mice were exposed to either filtered air or ETS during gestation, and their offspring were further exposed to HDM at 6–7 weeks old to induce allergic inflammation. Methylation in the promoter regions of allergic inflammation‐related genes and genomic DNA was quantified. Exposure to HDM resulted in the onset of allergic lung inflammation, with an increased presence of inflammatory cells, Th2 cytokines (IL‐4, IL‐5, and IL‐13), and airway remodeling. These asthmatic phenotypes were significantly enhanced when the mice had been exposed to in utero ETS. Furthermore, prenatal ETS exposure and subsequent HDM (ETS/HDM)‐induced asthmatic phenotypes agree with methylation changes in the selected asthma‐related genes, including IL‐4, IL‐5, IL‐13, INF‐γ, and FOXP3. Global DNA methylation was significantly lower in ETS/HDM‐exposed mice than that of controls, which coincides with the results observed in lung, spleen, and blood DNAs. Prenatal ETS exposure resulted in a severe increase in allergic inflammatory responses after an HDM challenge, with corresponding methylation changes. Prenatal ETS exposure may influence developmental plasticity and result in altered epigenetic programming, leading to an increased susceptibility to asthma. Environ. Mol. Mutagen. 58:423–433, 2017. © 2017 Wiley Periodicals, Inc.     

Differences in maternal behavior of rats and the sociosexual development of the offspring

This paper describes experiments designed to investigate long-term behavioral consequences for offspring of changes in maternal behavior directed toward them as pups. Specifically, the hypothesis was considered that experimentally induced alterations in maternal behavior would result in general and wide-ranging effects on offspring development, including effects on later social and sexual behavior. The first experiment looked at the effects of changing pup odors on maternal responsiveness toward the pups, and showed that the application of perfume, particularly to the anogenital region, resulted in significant lowering of maternal anogenital licking of pups. Non-pup-directed behavior did not differ between groups. The behavior of those pups that had thus differed in infant experience was then followed in three subsequent experiments. In Experiment 2, social behavior during the juvenile period was investigated, focusing particularly on the expression of social play. The most noticeable difference to emerge in this experiment was that male pups that had been anogenitally perfumed as infants showed much higher levels of social play than male or female pups from other treatment groups. The last two experiments considered adult behavior. Experiment 3 showed that there are no lasting effects of the neonatal treatment on the attractiveness an animal has for its conspecifics. In the final experiment, "masculine" sexual behavior of males (mounts with intromission), and "feminine" sexual behavior of females (i.e., lordosis and proceptive behavior) were investigated. This confirmed previous reports by Moore (1984) (Moore, C. L. (1984). Maternal contributions to the development of masculine sexual behavior in laboratory rats. Dev. Psychobiol., 17:347-363) that those male pups that had received lower rates of anogenital licking as pups showed longer intermount intervals, when tested as adults. The results are discussed in relation to the development of sexually differentiated behavior.