Perinatal maternal exposure to picrotoxin: effects on sexual behavior in female rat offspring

A previous study in our laboratory showed that perinatal maternal picrotoxin exposure (0.75 mg/kg) in rats improved heterosexual behavior in male offspring. In the present study, we examined the effects of this maternal treatment on sexual behavior in the female offspring. The dams received 0.75 mg/kg picrotoxin treatment (PT) once a day on the 18th and 21st day of pregnancy, 2 h after parturition and once a day during the first 4 days of lactation. The results showed that (1) at birth, the body weight and anogenital distance were not modified by treatment; (2) female sexual behavior was improved in experimental animals. These results demonstrate that perinatal picrotoxin exposure improves adult sexual behavior in female rat offspring as suggested by increase in the lordosis quotient.     

Maternal exposure to picrotoxin modifies the response of the GABAA receptor during sexual behavior of adult male rat offspring

This study investigated whether perinatal exposure to picrotoxin, a GABAA antagonist, modifies the effect of muscimol, a GABAA agonist, on the sexual behavior of adult male rats. Two hours after birth and then once daily during the next 9 days of lactation, dams received picrotoxin (0.75 mg/kg subcutaneously) or saline (1 ml/kg subcutaneously). The adult male offspring from the picrotoxin and saline groups received saline (1 ml/kg intraperitoneally) or muscimol (1 mg/kg intraperitoneally), and 15 min later, their sexual behavior was assessed. Muscimol treatment in the saline-exposed group increased the mount and intromission latencies. However, these effects were absent in the picrotoxin-exposed groups. The latencies to first ejaculation, postejaculatory mount, and intromission were decreased in both picrotoxin-exposed groups relative to the saline-exposed groups. The picrotoxin+muscimol-treated rats required more intromissions to ejaculate and the picrotoxin-exposed groups made more ejaculations than the saline-exposed groups. Thus, muscimol treatment did not increase the mount and intromission latencies following picrotoxin exposure, but increased the ejaculation frequency, which did not differ between the picrotoxin+muscimol and the picrotoxin+saline groups. These data indicate that perinatal picrotoxin treatment interfered with GABAA receptor development.     

Effects of exposure of rat dams to 1-bromopropane during pregnancy and lactation on growth and sexual maturation of their offspring

1-Bromopropane (1-BP) exhibits neuroreproductive toxicities in adult rats and humans. Here, we determined the effects of exposure of rat dams to 1-BP during pregnancy and lactation on the growth and sexual maturation of their offspring. In Experiment 1, 40 rats were exposed to 0, 100, 400 and 800ppm 1-BP during pregnancy and lactation for 8h/day. Ten rats that were not placed in chambers throughout the experiment served to observe the effect of separation of dams from offspring. In Experiment 2, three groups of 10 pregnant rats each were exposed to fresh air in three chambers and 10 other rats were exposed to 800ppm 1-BP during pregnancy and lactation for 8h/day. After delivery, offspring of the exposed and non-exposed dams were swapped so that they were nursed by the opposite dams. In Experiment 1, the survival rate and body weight of offspring were lower than the non-exposed in 1-BP dose-dependent manner. In Experiment 2, the survival rate and body weight of offspring (Group A) nursed by exposed dams and those (Group B) of exposed dams were significantly lower than non-exposed groups. The body weight of Group A was lower than that of Group B, although the two groups showed a significant equal decrease in the survival rate. The number of dead offspring from Group A was significantly higher. Our results indicate that exposure to 1-BP during pregnancy and lactation has comparable effects on survival rate, but exposure during lactation has a more adverse effect on growth of offspring than that during pregnancy. Moreover, exposure during lactation is associated with reduced early survival of third generation (F2) rats.     

The effect of maternal exposure to methamphetamine during pregnancy and lactation period on hippocampal neurons apoptosis in rat offspring

Methamphetamine (METH) is a highly addictive stimulant. The effect of maternal exposure of METH on apoptosis in rat hippocampus was evaluated. Wistar rats were randomly divided into: 1&;2) Rats were given METH during pregnancy or breastfeeding (5?mg/kg i.p.), 3&;4) Rats injected with normal saline and 5&;6) Rats served as control. TUNEL method was used to evaluate apoptotic cells. Mean number of apoptotic cells was significantly increased in CA1, CA3 and DG regions. The CA1 field was significantly improved in the experimental pregnancy and breastfeeding groups. The study showed that METH causes apoptosis in all three hippocampal fields, especially CA1 region.     

Impaired oligodendroglial development by decabromodiphenyl ether in rat offspring after maternal exposure from mid-gestation through lactation

Pregnant Sprague–Dawley rats were given diet containing decabromodiphenyl ether (DBDE) either at 0, 10, 100, or 1000 ppm from gestation day (GD) 10 until day 20 after delivery (PND 20). No significant alterations were observed in maternal and offspring reproductive parameters. At PND 20, serum triiodothyronine concentrations examined in males were slightly reduced at 1000 ppm (84.2% of the control value), and incidence of thyroid follicular cell hypertrophy was increased in both sexes with significant difference in males at 1000 ppm. Diffuse liver cell hypertrophy accompanying increased relative liver weight and increased cytoplasmic eosinophilia of the renal proximal tubules were observed in both sexes with significant difference from 10 ppm in males and females, respectively. At postnatal week 11, serum thyroxine concentrations examined in males were slightly reduced at 1000 ppm (85.9% of the control value), and the incidence of thyroid follicular cell hypertrophy was non-significantly increased from 10 ppm in males. There were reductions in the corpus callosum area and density of 2′,3′-cyclic nucleotide 3′-phosphodiesterase-immunoreactive oligodendrocytes in the cingulate deep cortex in males from 100 ppm. Conversely, NeuN-immunoreactive neuronal distribution in the hippocampal CA1 was unchanged. This suggests that developmental DBDE-exposure caused irreversible white matter hypoplasia targeting oligodendrocytes from 100 ppm, accompanied with developmental hypothyroidism. The lowest-observed-adverse-effect level of DBDE was determined to be 10 ppm (0.7–2.4 mg/kg-body weight-d).     

Effects of maternal exposure to a low dose of diethylstilbestrol on sexual dimorphic nucleus volume and male reproductive system in rat offspring

Diethylstilbestrol (DES) was administered subcutaneously at 0.5, 1.5 or 4.5 microg/kg/day (DES 0.5, 1.5 and 4.5 groups, respectively) to pregnant SD rats daily on days 7-21 of gestation, to investigate its effects on the development and functions of the reproductive system in their male offspring. Of the 10 pregnant rats in the DES 4.5 group, only 1 delivered, and this rat could not suckle the pups. Rat pups in the DES 0.5 and 1.5 groups were autopsied at 1, 3, 6 and 15 weeks after birth. The testosterone concentrations in the DES 1.5 and 0.5 groups at 6 weeks were significantly decreased and the plasma LH concentrations were not altered. In the DES 1.5 group, DES treatment did not change the volume of the sexually dimorphic nucleus in the preoptic area (SDN-POA) in the male offspring, although this dose of DES increased the volume of SDN-POA in female offspring. The DES treatment altered frequencies in the cycles of the seminiferous tubules, and suppressed histological maturation in the epididymis and the prostate weight. These observations indicate that prenatally administered DES impairs testicular endocrine function continuously as well as pituitary function, but the induced low level of testosterone disrupts spermatogenesis and permanently inhibits the morphological development of epididymis and prostate.     

Limited lactational transfer of acrylamide to rat offspring on maternal oral administration during the gestation and lactation periods

To evaluate the developmental exposure effects of acrylamide (ACR) on the nervous and male reproductive systems, pregnant Sprague-Dawley rats were given ACR at 0, 25, 50 or 100 ppm in the drinking water from gestational day 6 to postnatal day (PND) 21 and histopathological assessment was performed at PND 21. Exposure levels in offspring were examined by measurement of free ACR and hemoglobin (Hb)-ACR adducts on PND 14, and compared with maternal levels on PND 21. Additionally, a group of offspring that received ACR at 50 mg/kg by intraperitoneal injections directly three times a week from PND 2 to 21 was subjected to analysis for comparison with maternal exposure groups. Although maternal neurotoxicity was evident at 100 ppm, no changes suggestive of neurotoxicity or testicular toxicity were observed in their offspring except for growth retardation evident as lowered body weights. In contrast, offspring given ACR intraperitoneally exhibited obvious neurotoxicity, but not testicular damage. Free ACR in serum and milk was detected in neither dams nor their offspring. The level of ACR-Hb adducts in offspring was one tenth or less than that in dams. In summary, although preweaning rats have susceptibility to ACR-induced neurotoxicity, the internal level of ACR in offspring exposed through maternal oral administration is insufficient to induce neurotoxicity and testicular toxicity due to limited lactational transfer.     

Maternal nicotine exposure during gestation and lactation induces cardiac remodeling in rat offspring

The aim of this study was to evaluate the effects of maternal nicotine exposure on heart morphology and fibrosis in rat offspring. Nicotine was administered to pregnant Sprague-Dawley rats by using a subcutaneous osmotic mini-pump at a dose of 6 mg/kg/day from Gestational Days 7–21 or Gestational Day 7 to Postnatal Day 14. A control group received an equal volume of saline by the same route as nicotine. Rats born to prenatal nicotine-treated dams exhibited significantly greater cell width of cardiomyocytes, fewer cardiomyocyte nuclei number, higher β-myosin heavy chain and transforming growth factor (TGF-β1) expression, and higher collagen deposition in heart compared with rats born to normal saline-treated dams on Postnatal Days 7 and 21. Postnatal nicotine exposure further enhances these effects. We conclude that TGF-β1 may be involved in the pathogenesis of cardiac remodeling induced by maternal nicotine exposure during gestation and lactation in rat offspring.     

Effects of silver nanoparticles prenatal exposure on rat offspring development

Many types of nanocomposites employed in food packaging are based on silver nanoparticles (AgNP) because of their antibacterial properties, which can increase food shelf-life. As the commercialization of AgNP products has been expanding, the released of such nanoparticles in the environment has caused enormous concern, once they can pose potential risks to the environment and human beings. For instance, exposure of the maternal environment to nanomaterials during pregnancy may impact the health of the dam, fetus and offspring. In this context, here we investigated the effects of prenatal exposure of AgNP on the pregnancy outcomes of dams and postnatal development of their offspring. Pregnant Wistar rats were exposed to distinct AgNP concentrations (0, 1, 3 and 5 μg/kg/day) from beginning to the end of pregnancy. At parturition, newborns were observed regarding clinical signs of toxicity and survival rate. The offspring was examined by evaluating developmental endpoints. A delay in time for vaginal opening and testes descent were detected in the offspring exposed to AgNP during embryonic development. Our results indicate that prenatal exposure to AgNP can compromise neonatal rats’ postnatal development, especially the reproductive features.     

The effects of exposure to diazepam during various stages of gestation or during lactation on the development and behavior of rat pups

In the present study we have investigated the effects of diazepam (DZP) (10 mg/kg) treatment of rat dams during different periods of gestation or during lactation on the development and behavior of their offspring. The results show that DZP exposure during different phases of early development has differing effects on later behavior. Exposure during mid-gestation resulted in early and transient hyperactivity, but no learning or memory deficits at 2 months of age were observed. However, both late prenatal and early postnatal exposure to DZP resulted in significant behavioral changes. Late prenatal treatment caused no hyperactivity but resulted in poor performance on the learning and retention of a choice discrimination task, while early postnatal exposure resulted in consistent and lasting hyperactivity and in substantial discrimination learning and retention deficits at 2 months of age.     

Effects of a maternal diet supplemented with chocolate and fructose beverage during gestation and lactation on rat dams and their offspring

1. Consumption of a high-fat and high-energy diet during pregnancy leads to a risk of long-term consequences on fetal development, as well as on the postnatal health of offspring. To investigate the effects of such a diet on fetal programming, we established a high-energy intake pregnant rat model using chocolate and fructose beverage as supplements to a normal chow diet. 2. Pregnant Sprague-Dawley rats were assigned to either chow (control) or a diet supplemented with chocolate and fructose beverage throughout gestation and lactation. The male F(1) pups received normal chow diet after weaning. Physiological or pathological changes in dams and pups (e.g. glucose and lipid metabolism) were evaluated. 3. The results showed that dams offered the high-fat (mainly from chocolate) and high-calorie diet during gestation consumed more energy and gained more weight than chow-fed dams. Over-consumption of chocolate reduced chow intake in dams, leading to low maternal protein supply. As a result, pups from these dams exhibited reduced birth weight that lasted until adulthood. The high-energy diet during lactation led to increased total body fat, as well as impaired liver function, in offspring; thus, the lactational diet is suggested to be a stronger determinant of offspring fat metabolism than gestational diet. 4. The results of the study suggest that over-supply of carbohydrates, such as chocolate and fructose, either during gestation or lactation has a negative impact on the well-being of offspring.     

Chronic oxytocin treatment during late gestation and lactation impairs development of rat offspring

The nonapeptide oxytocin (OT) plays an important role in timing and course of parturition, and in milk ejection during lactation. Exogenously enhanced OT levels were reported to impair body development of rat offspring at birth and during postnatal stages. In the present study, this effect was further investigated by giving pregnant rats of postcoital day 17 a SC implant that delivers small amounts of OT for 2 months (approximately threefold enhancement of OT levels), and by introducing a crossfostering protocol for the offspring. A slightly reduced body weight of 5 to 7% was again observed in pups born to OT-implanted dams. When reared postnatally by OT-treated mothers, pups lost weight gain (− 7 to −10%). During the weaning period, however, body size caught up with that of control animals. When nursed by an untreated mother, this recovery took place before that period. Growth of control offspring was also hampered when placed with OT-treated mothers, but these pups failed to recover from low body weights which lasted up to at least 70 days of age (−7%). Daily urine production of the pups born of and reared by the OT-treated mothers was reduced at 1 month of age, but this effect was only transient and had disappeared at 70 days of age. Notwithstanding, the recovery of body growth, brain sizes, and cerebellar DNA, i.e., cell content was reduced in the pups born and reared by OT-treated mothers, indicative of a lasting effect on brain development. Such late brain changes were not observed in pups of OT-treated mothers nursed by untreated mothers, and in control pups nursed by both types of mothers. In conclusion, one might say that physiologically enhanced levels of maternal OT can induce subtle alterations in brain development that are potentially indicative for lasting physiological and behavioral changes in the offspring.     

Effects of maternal exposure to diethylstilbestrol on the development of the reproductive system and thyroid function in male and female rat offspring

Diethylstilbestrol (DES) was administered subcutaneously at 1.5 or 15 microg/kg/day (DES 1.5 group, DES 15 group) to pregnant SD rats daily on days 7-21 of gestation to investigate its effects on the development and functions of the reproductive system and thyroid gland in their offspring. Of the 11 pregnant rats in the DES 15 group, only one delivered a live pup. Rat pups in the DES 1.5 group were autopsied at 1, 3, or 6 weeks after birth. In the DES 1.5 group, the plasma T4 concentrations at all weeks of age at autopsy were significantly increased, the TSH concentration at 6 weeks of age was also significantly increased, and the height of thyroid follicular epithelial cells was increased at 3 weeks. The testosterone concentration in the DES 1.5 group at 6 weeks was significantly decreased and the plasma LH concentration was increased. The DES treatment increased the plasma FSH concentration in female pups at 3 weeks, increased the percentages of primary and secondary ovarian follicles, and decreased the percentage of primordial follicles, but did not influence the timing of the vaginal opening or the onset of the estrous cycle. These observations indicate that prenatally administered DES increases thyroid function, and has an inhibitory effect on testicular function and a promoting effect on female reproductive function.     

Maternal lead exposure during lactation persistently impairs testicular development and steroidogenesis in male offspring

Lead (Pb) is a testicular toxicant. In the present study, we investigated the effects of maternal Pb exposure during lactation on testicular development and steroidogenesis in male offspring. Maternal mice were exposed to different concentration of lead acetate (200 or 2000 ppm) through drinking water from postnatal day (PND) 0 to PND21. As expected, a high concentration of Pb was measured in the kidneys and liver of pups whose mothers were exposed to Pb during lactation. In addition, maternal Pb exposure during lactation elevated, to a less extent, Pb content in testes of weaning pups. Testis weight in weaning pups was significantly decreased when maternal mice were exposed to Pb during lactation. The level of serum and testicular T was reduced in Pb‐exposed pups. The expression of P450scc, P450_17α and 17β‐HSD, key enzymes for T synthesis, was down‐regulated in testes of weaning pups whose mothers were exposed to Pb during lactation. Interestingly, the level of serum and testicular T remained decreased in adult offspring whose mothers were exposed to Pb during lactation. Importantly, the number of spermatozoa was significantly reduced in Pb‐exposed male offspring. Taken together, these results suggest that Pb could be transported from dams to pups through milk. Maternal Pb exposure during lactation persistently disrupts testicular development and steroidogenesis in male offspring. Copyright © 2012 John Wiley & Sons, Ltd.     

Maternal cypermethrin exposure during lactation impairs testicular development and spermatogenesis in male mouse offspring

Within the last decade, numerous epidemiological studies have demonstrated that endocrine disruptors are a possible cause for a decline in semen quality. Cypermethrin is a widely used pyrethroid insecticide, but little is known about its potentially adverse effects on male reproduction. In the present study, we investigated the effects of maternal cypermethrin exposure during lactation on testicular development and spermatogenesis in male offspring. Maternal mice were administered with cypermethrin (25 mg/kg) by gavage daily from postnatal day 0 (PND0) to PND21. Results showed that the weight of testes at PND21 was significantly decreased in pups whose mothers were exposed to cypermethrin during lactation. Maternal cypermethrin exposure during lactation markedly decreased the layers of spermatogenic cells, increased the inside diameter of seminiferous tubules, and disturbed the array of spermatogenic cells in testes of pups at PND21. In addition, maternal cypermethrin exposure during lactation markedly reduced mRNA and protein levels of testicular P450scc, a testosterone (T) synthetic enzyme. Correspondingly, the level of serum and testicular T at weaning was significantly decreased in pups whose mothers were exposed to cypermethrin during lactation. Although the expression of testicular T synthetic enzymes and serum and testicular T in adulthood had restored to control level, the decreased testicular weight and histological changes were irreversible. Importantly, the number of spermatozoa was significantly decreased in adult male offspring whose mothers were exposed to cypermethrin during lactation. In conclusion, maternal cypermethrin exposure during lactation permanently impairs testicular development and spermatogenesis in male offspring, whereas cypermethrin‐induced endocrine disruption is reversible. © 2010 Wiley Periodicals, Inc. Environ Toxicol 2011.     

Impaired female sexual behavior of rat offspring exposed to Solanum lycocarpum unripe fruits during gestation and lactation: lack of hormonal and fertility alterations

Solanum lycocarpum St. Hil (Solanaceae) is an invasive and native shrub very common in the Brazilian savanna. It is well known that this plant contain steroidal glycoalkaloids that can be transformed into an intermediate for steroidal drugs production, like oral contraceptives. In this way, it is very possible that these glycoalkaloids and its aglycone, once in the body by ingestion of S. lycocarpum fruits, may act disrupting to the endocrine system. Rat offspring were exposed to S. lycocarpum unripe fruits (10% in the diet) from gestational day (GD) 06 to post-natal day (PND) 07. The female exposed offspring showed, at adult age (PND 100), impaired sexual behavior. However, the fecal hormonal metabolite levels, measured at PND 30, PND 60 and PND 90, and the fertility (PND 120) of male and female experimental offspring were normal. We can assume that the steroidal glycoalkaloids, solamargine and solasodine, present in the fruit, are degradated, once inside the organism, to the steroidal alkaloid solasodine, which may penetrate, by simple diffusion, the placental and/or the hematoencephalical barriers and impact the fetuses. Finally, S. lycocarpum fruit may act as phytohormones, promoting perhaps some neural alterations that at adult age may impair the sexual behavior of the experimental female without impairing the fertility and sexual hormone synthesis. These changes observed can be the direct consequence of the toxic actions of the steroidal alkaloid on the female offspring during fetal development.     

Concurrent exposure to aluminum and stress during pregnancy in rats: Effects on postnatal development and behavior of the offspring

The present study was conducted to assess the potential combined influence of maternal restraint stress and aluminum (Al) exposure on postnatal development and behavior in the offspring of exposed rats. Female rats were concurrently exposed to 0 (control group), 50 or 100 mg/kg/day of Al administered as Al nitrate nonahydrate in drinking water with citric acid (355 or 710 mg/kg/day) for a period of 15 days prior to mating with untreated males. Aluminum exposure was maintained throughout the gestational, lactational and post-weaning periods. On days 6-20 of gestation, one-half of the pregnant animals in each group were restrained for 2 h/day. Food consumption and maternal body weight were decreased in the groups exposed to restraint only or combined with the highest Al dose. All of the animals were allowed to deliver and wean their offspring. The pups were evaluated for physical development and neuromotor maturation. Moreover, open-field activity, passive avoidance, and spatial learning in a water maze were also determined on postnatal days 30, 35 and 60, respectively. Body weight of pups treated with 100 mg/kg/day of Al was decreased relative to controls from postnatal day 12 through 21, sexual maturation was delayed in Al treated females and in males exposed to 100 mg/kg/day. Forelimb grip strength was reduced in males exposed to 100 mg/Al/kg/day and in females exposed to this Al dose plus prenatal restraint. Learning in a passive avoidance task indicated facilitated performance for Al treated rats at 100 mg/kg/day combined with prenatal restraint as evidenced by longer avoidance latencies, while learning in a water maze task showed a shorter latency to find the platform on acquisition day 2 for Al treated rats. However, no effects of Al on water maze performance were detected during the retention probe trial in which the only effect noted was an increase in the platform quadrant swim time for the prenatal restraint group. In general terms, the results of the present study did not show a notable influence of maternal restraint on the Al-induced postnatal developmental and behavioral effects in the offspring of prenatally Al-exposed rats.     

Prenatal exposure to dichlorvos: physical and behavioral effects on rat offspring

The effects of prenatal exposure to dichlorvos (DDVP), an organophosphate (OP) pesticide, on pups' physical and neurobehavioral developments were investigated. Forty pregnant rats were treated by gavage with 8.0 mg/kg DDVP or its vehicle (1 ml/kg) from the 6th to the 15th day of pregnancy. At birth, pups were weighed, the litters culled to eight animals (four male and four female), and then observed for physical (pinna detachment, incisor eruption, eye opening, testes descent, and vaginal opening) and neurobehavioral developments (palmar grasp, surface righting, negative geotaxis, and open-field behaviors). As adults, open-field, apomorphine-induced stereotypy, and passive avoidance behaviors were also assessed. Results showed no differences between the body weight of DDVP and control-treated groups. No differences were observed on the measures of physical and neurobehavioral development. Locomotor activity of male pups at 21 days of age was decreased by DDVP exposure. Adult experimental offspring showed a decreased locomotor frequency and an increased immobility duration on open-field behavior in relation to control animals; the apomorphine-induced stereotyped behavior was decreased by the pesticide exposure as well as performance on the passive avoidance task. These data suggest that prenatal DDVP exposure was able to decrease offspring motor function (adolescence and adults) and conditioned response learning, probably by interference with the cholinergic-dopaminergic balance of activity involved with the control of motor function as well as the cholinergic system that modulates learning process.     

Gestational ethanol and nicotine exposure: effects on maternal behavior, oxytocin, and offspring ethanol intake in the rat

Alcohol consumption and smoking during pregnancy is common, despite the known adverse effects of these drugs on fetal development. Though studies on the effects of each drug separately are published, little is known about the effect of concurrent use of alcohol and nicotine in humans or in preclinical models. In this report, we examined the impact of continuous gestational exposure to both ethanol via liquid diet and nicotine via an osmotic minipump on maternal behavior, offspring ethanol intake, and oxytocin levels in a rat model. Dams were tested for the onset of maternal behavior with litters of unexposed surrogate pups and then killed to examine oxytocin levels within specific brain regions. Drug-exposed offspring reared by surrogate dams were tested for ethanol intake at either adolescence or adulthood, and oxytocin levels were measured in relevant brain regions after behavioral tests. Dams exhibited minor deficits in maternal care, which were associated with lower oxytocin levels in both the ventral tegmental and medial preoptic areas compared to control dams. Prenatal exposure altered sex-specific ethanol intake, with differential effects at adolescence and adulthood. Oxytocin system changes were also apparent in the ventral tegmental and medial preoptic regions of drug-exposed adolescent and adult offspring. These results suggest that dam treatment with ethanol and nicotine can somewhat negatively affect the early rearing environment, and that prenatal exposure to both of these drugs results in drinking behavior differing from what would be expected from either drug alone. Oxytocin's possible involvement in the mediation of these effects is highlighted.