Effects of Prenatal Rubratoxin-B Exposure on Behaviors of Mouse Offspring

Takahide Kihara*,1, Tien W. Surjono{dagger}, Michiko Sakamoto*, Takuya Matsuo*, Yoshiko Yasuda* and Takashi Tanimura{ddagger},2

* First Department of Anatomy, Kinki University School of Medicine, Osakasayama, Osaka, 589-8511, Japan; and {dagger} Division of Animal Morphogenesis, Department of Biology, Faculty of Mathematics and Sciences, Bandung Institute of Technology, Bandung, Indonesia; and {ddagger} Kinki University, Osakasayama, Osaka, 589-8511, Japan

Received November 29, 2000; accepted February 15, 2001


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The effects of prenatal rubratoxin-B (RB) exposure on 8 behavioral parameters in Jcl:ICR mice were assessed. Pregnant mice were injected intraperitoneally with 0.1 or 0.2 mg/kg/day of RB dissolved in propylene glycol water solution on days 7–9 (Group A) or 10–12 (Group B) of gestation. Controls received the vehicle similarly on days 7–12 of gestation. Before weaning, the offspring of both sexes were examined to test their the surface righting reflex (5 days of age), cliff avoidance response (6 days), negative geotaxis response (7 days), and swimming development (8, 10, and 12 days). After weaning, male animals were examined using the rotarod test (6 weeks of age), the open-field test (7 weeks), the shuttle-box-avoidance-learning test (9 weeks), and the water E-maze test (10 weeks). The preweanling offspring in the 0.2 mg/kg-B group showed significantly lower success rates and longer response times than controls in the cliff-avoidance response. In swimming development, the offspring in the 0.2 mg/kg B group had significantly lower scores than controls for swimming angle at 10 and 12 days of age. The avoidance learning of the mice in all RB-exposed A and B groups was significantly poorer than that of controls. These results indicate that prenatal exposure to RB produced a delay of early response development and impaired learning ability in the offspring of mice exposed to RB during middle pregnancy.

Key Words: rubratoxin B; mycotoxin; prenatal exposure; behavioral teratology; developmental neurotoxicity; mouse.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rubratoxin B (RB) is a mycotoxin produced by fungi such as Penicillum rubrum and P. purpurogenum, which are common soil fungi that sometimes contaminate animal feeds (Wilson and Harbison, 1973Go). RB is hepatotoxic, nephrotoxic, and splenotoxic in several animals (Burnside et al., 1957Go; Engelhardt et al., 1987Go, 1988Go; Lockard et al., 1981Go; Wogan et al., 1971Go), and is mutagenic in the mouse (Evans and Harbison, 1977Go), and induces necrosis of the thymus, lymph node, spleen, and bone marrow of the mouse (Natori et al., 1970Go), but is not carcinogenic (Wogan et al., 1971Go).

The developmental toxicity of RB has been studied in 3 species (for review see, Hood, 1979; Hood and Szczech, 1983). RB has been reported to be teratogenic and/or embryotoxic in mice (Evans and Harbison, 1977Go; Hayes and Hood, 1976Go; Hood, 1986Go; Hood et al., 1973Go; Koshakji et al., 1973Go; Wilson and Harbison, 1973Go), in hamsters (Hayes and Hood, 1976Go), and in chick embryos (Gilani et al., 1979Go). A previous study in our laboratory demonstrated that RB induced gross malformations, internal anomalies, skeletal malformations, embryo lethality, intrauterine growth retardation, increased skeletal variations, and delayed ossification in the mouse fetuses of dams injected intraperitoneally with doses 0.6 or 1.2 mg/kg/day on one of days 6–9 of gestation (Surjono, et al., 1985Go).

In the past 20 years, the importance of postnatal evaluation for studying behavioral teratology has received increasing recognition, and the test battery system for assessment of behavioral teratogenic potential in reproductive and developmental toxicity studies has been widely used (Meyer, 1998Go; Riley and Vorhees, 1986Go; Tanimura, 1992Go; Ulbrich and Palmer, 1996Go; Voorhees, 1997). However, there are no published data known to us on the behavioral teratogenic effects of RB in animals and humans.

The present study, therefore, was conducted to determine the behavioral teratogenic effects on the mouse offspring of dams injected intraperitoneally with 2 macroscopically subteratogenic doses of RB during early or mid organogenesis, by using a behavioral test battery system for functional evaluation (Fox, 1965Go; Kihara, 1991Go; Kihara et al., 1995Go; Vorhees et al., 1979aGo,bGo).


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animals and treatments.
Nine-week-old male (35–37 g) and female (27–30 g) Jcl:ICR mice were purchased from Clea Japan, Osaka, Inc., and acclimated to the laboratory for 2 weeks prior to mating. Pellet diet OA-2 (Clea Japan) and tap water were available at libitum. Animals were maintained in a room with a controlled temperature of 23 ± 2°C, a relative humidity of 50 ± 10%, and a 12-h light:dark cycle (lights on at 07:00 A.M.). Eleven-week-old females were mated overnight for 15 h with one male each. Mating was confirmed if a vaginal plug was observed. The following morning (day 0 of gestation), the pregnant mice were assigned randomly to 1 of 5 groups. They were individually housed in clear polycarbonate cages with stainless-steel wire lids, with wooden shavings as bedding provided throughout gestation and lactation and left undisturbed, except for treatment and weighing, until parturition.

Pregnant mice were injected intraperitoneally with 0.1 (low dose) or 0.2 (high dose) mg/kg/day of RB (Makor Chemicals Ltd., Jerusalem, Israel) dissolved in propylene glycol (Wako Pure Chemical Industries, Ltd., Osaka)-water (1:1) solution on days 7–9 (Group A) or 10–12 (Group B) of gestation. Control animals received vehicle-only intraperitoneally on days 7–12 of gestation. The treatment volume was 10-ml/kg body weight. Fresh solutions of RB were prepared on the day of use.

The dams were allowed to deliver spontaneously and rear their offspring until weaning. At 4 days after birth, litters were culled randomly to groups of 8 offspring, with the same number of males and females, as far as possible. At 21 days, the offspring were weaned, separated by sex, and housed with 4 littermates of the same sex. Markings were used to identify all offspring with dry ink before weaning, and with picric acid-ethanol solution after weaning.

Body weight and physical landmarks.
The dams were weighed on 0, 14, and 18 days of gestation, daily during treatment, and on days 0, 4, 7, 14, and 21 after delivery. After weaning their litters (21 days after delivery), all the dams were killed by ether overdose, and were examined for number of implantation sites and any abnormalities of the reproductive organs. At birth, all live and dead offspring were counted. Live offspring were weighed, sexed, and examined for external malformations. The live offspring were again counted and weighed on days 4, 7, 14, and 21 after birth. After weaning, all offspring were counted and weighed weekly until 10 weeks of age.

The following physical landmarks were noted: bilateral pinna unfolding at 4–6 days of age, abnormal hair emergence and low incisor eruption at 7–9 days, eye opening at 14–16 days, descent of both testes in males at 21–23 days, and vaginal opening at 28–30 days in females.

Behavioral test battery.
The behavioral tests and ages at testing are listed in Table 1Go. All the behavioral testing procedures were conducted blind with regard to the treatment groups, and tests were performed between 9:00 A.M. and 1:00 P.M. Only post-weanling males were used in order to exclude possible influence of the estrus cycle on behavioral performance.


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TABLE 1 Schedule of Behavioral Test Battery
 
Surface righting reflex.
Each mouse was placed on its back on a flat surface and released. The amount of time required to regain all 4 paws in contact with the surface was recorded on a stopwatch. Each offspring was tested in 2 trials each day. The maximum time allowed per trial was 30 s (Fox, 1965Go; Kihara, 1991Go; Vorhees et al., 1979aGo,bGo). The number of mice with successful responses under 2 s was recorded.

Cliff avoidance.
Each animal was placed on a table edge with the forepaws and nose over the edge. The amount of time required to complete backing and turning away from the edge was recorded. Each offspring was tested in 1 trial. The maximum time allowed per trial was 60 s (Fox, 1965Go; Kihara, 1991Go; Vorhees et al., 1979aGo,bGo). The number of animals with successful responses within 30 s was recorded.

Negative geotaxis.
The time taken to complete a 180-degree turn when placed in a head-down position on a 25-degree inclined plywood surface was measured. Each animal was given one trial (Fox, 1965Go; Kihara, 1991Go; Vorhees et al., 1979aGo,bGo).

Swimming development.
This procedure has been described elsewhere (Fox, 1965Go; Kihara, 1991Go; Rice and Millan, 1986Go; Vorhees et al., 1979,bGo). Each mouse was individually placed in a tank of water (28°C) for 5–10 s and the angle in the water (head position), direction, and limb usage were observed and scored.

Rotarod test.
The apparatus consisted of a rod 3 cm in diameter, which had a hard rubber surface and was linked to a variable-speed motor. The top of the rod was 34 cm above the back of the apparatus (Shinano Seisakusho Ltd., Tokyo, SN-498). Animals were placed individually on the rod for at least 5 s, and the rod was rotated at speeds of 5 or 15 rpm. Animals were tested in 2 trials per day for 2 consecutive days. The maximum trial duration was 180 s, and the inter-trial interval was about 30 min. The time that each animal remained on the rod at each rotation speed was recorded (Kihara, 1991Go).

Open-field test.
Mice were tested in a circular open field (100-cm diameter circular black polyvinyl chloride) on 3 consecutive days for 180 s per day. The time to leave the start area (latency), number of sections entered with all 4 legs (ambulation), number of rearings, and number of fecal boluses were recorded (Kihara, 1991Go).

Conditioned avoidance learning test.
The apparatus used was a 2-way shuttle box (48WX22DX20.5H, Takei Kiki Kogyo, Co., Tokyo). The box was divided into equal compartments by a metal partition. The grid floor of each compartment consisted of stainless steel rods spaced 0.7 cm center-to-center. An electric shock could be delivered though the grid floor.

As an auditory warning device, a commercial buzzer (about 90 dB) was placed in a central position between the 2 boxes. The conditioned-avoidance schedule was as follows: after adaptation for 1 min in one side-compartment, a 10-s warning duration (conditioned stimulus; CS), and electric shock (approximately 85 V, 0.5 mA, 60 Hz, Ac; unconditioned stimulus; UCS) for a maximum of 10 s, and a 20-s inter-trial interval (ITI). Crossing to the opposite side compartment during the CS period immediately terminated the stimuli and foot shock was avoided. Both crossing to the other compartment at times other than the CS presentation period, and no-crossing to the other compartment were ineffective. Each session consisted of 20 consecutive trials per day, and animals were tested on consecutive days for 4 sessions. The number of conditioned avoidance responses and first start latency time were recorded, and the mean percent of avoidance responses per day was calculated.

Water E-maze test.
The E-shaped maze apparatus consisted of a gray polyvinyl chloride, 50 cm in breadth (back wall), middle arm (start point) 50 cm from front to back wall, both right and left arms each measuring 30 cm long and 10 cm in alley width. The escape ramp (wire mesh, on the ends of the arms) was not visible from the choice point. The maze was filled to a depth of about 20 cm with water maintained at a temperature of 22°C.

On the first day of testing, at the first trial, an escape ramp was placed in each of the right and left arms. From the second to the sixth trial, the escape ramps were placed in opposite positions from the first trial. On the second and third days, the escape ramps were in the same position, and on the fourth day, the escape route was reversed. The inter-trial interval was approximately 30 min. The swimming time and the number of errors in the maze were recorded for each trial.

Brain weight.
One male offspring from each litter was killed at 11 weeks of age by ether overdose and autopsied, and the brains were removed and weighed.

Statistical analysis.
The number of implantation sites and live offspring, as well as the body weight of dams and offspring, were analyzed by 1-way analysis of variance (ANOVA), followed by Scheffe`s test if differences were found. The survival-index data were analyzed by the Chi-square test. The behavioral measures, and physical developmental observations were evaluated by using the Mann-Whitney U test for nonparametric comparison of group means (Siegel, 1956Go; Sokal and Rohlf, 1973Go). Before weaning, the data from individual subjects were averaged, and the litter was used as the unit of analysis. After weaning, the analyses were performed on the basis of individual animals from each litter. The accepted level of significance was p < 0.05.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Maternal Effects
Neither death nor noticeable symptoms were observed in the dams of any group throughout gestation and lactation. RB had no significant effect on the length of either gestation or the lactation period (data not shown).

Growth and Physical Landmarks of the Offspring
There were no significant differences between the RB groups and the control group with regard to the number of implants or live births, sex ratio of offspring, offspring with external malformations, or survival rates at 4 or 21 days of age (at weaning), or at 10 weeks of age. At birth, the body weights of both male and female offspring in the 0.2-mg/kg B group, and at weaning, the body weight of female mice in the 0.2-mg/kg B group were significantly lower than those of controls. However, there were no significant differences between the RB groups and the control group at 4 and 7 days of age (data not shown), or at 21 days or 10 weeks of age in the male offspring (Table 2Go).


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TABLE 2 Reproductive Performance of the Dams Exposed to Rubratoxin B, and Survival and Body Weight in Mouse Offspring
 
With regard to physical landmarks, there were no significant effects of RB-exposure on pinna unfolding, hair emergence, incisor eruption, eye opening, testis descent, or vaginal opening (data not shown).

Behavioral Testing
There were no sex differences on any preweaning tests; therefore, males and females were combined for data analysis. The values are presented as the mean of the litter means in Tables 3 and 4GoGo.


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TABLE 3 Reflex Development of Preweaning Mouse Offspring of Dams Exposed of Rubratoxin B
 

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TABLE 4 Swimming Development in Preweaning Mouse Offspring of Dams Exposed to Rubratoxin B
 
Reflex behavior.
The results of reflex testing are presented in Table 3Go. The 0.2-mg/kg B offspring were less successful in cliff avoidance than control offspring, and also had significantly slower response times. Cliff avoidance was not affected in the other RB-exposure groups. For the surface-righting and negative-geotaxis reflexes, there were no significant differences between the RB-exposed groups and the control group.

Swimming development.
The results are shown in Table 4Go. With regard to swimming angle in the water, the 0.2-mg/kg B group scored significantly lower than the control group at 10 and 12 days of age, but at 8 days of age, there was no significant effect of exposure. There were no significant differences between the RB-exposed groups and the control group for swimming direction and limb usage at 8, 10, or 12 days of age.

Rotarod performance.
There were no significant differences between the RB-exposed groups and the control group for remaining on the rotarod at 5 or 15 rpm on either the first or second test day (data not shown).

Open field activity.
There were no significant differences between the RB-exposed groups and the control group for ambulation counts, rearing and defecation frequencies, or the start-latency time on any of the test days (data not shown).

Conditioned avoidance learning.
The mean avoidance rates in the RB-exposed groups were lower than those in the control group at the second, third and fourth training sessions. The conditioned-avoidance test is presented in Figure 1Go. The RB-exposed groups showed significantly lower avoidance rates than the control group at the third and fourth sessions.



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FIG. 1. Acquisition of shuttle box conditioned avoidance response in male mouse offspring of dams exposed to rubratoxin B. Changes in the mean avoidance rates are shown. (A) exposure on days 7–9 of gestation; (B) days 10–12; control (vehicle): days 7–12; number of offspring tested listed in parentheses. Vertical bar represents the mean standard error. *Significantly different from the control (p< 0.05).

 
Water E-maze.
There were no significant differences between the RB-exposed groups and the control group for swimming time or the number of errors on any of the trial days (data not shown).

Brain Weight
There were no significant differences in brain weights between the RB-exposed groups and the control group (data not shown).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
No information is available concerning the effects of prenatal RB exposure on behavioral performance in experimental animals and humans. The present study is the first to show that prenatal exposure to RB affects motor development in preweanling offspring and alters the rate of acquisition of a conditioned avoidance-learning task in the offspring. Treatment with RB at the higher dose during mid organogenesis (days 10–12), but not during early organogenesis (days 7–9), delayed the development of the cliff-avoidance response. Swimming ontogeny is a measure of the development of neuromotor coordination and swimming ability (Kihara, 1991Go; Schapiro, 1970Go; Vorhees et al., 1979aGo,bGo). In the present study, prenatal RB exposures at the higher dose during mid-organogenesis (days10-12) also resulted in a delay in the direction of swimming but exposure during early organogenesis (days 7–9) caused no such delay. On the other hand, exposed and control mice performed similarly in the surface righting reflex and negative geotaxis tests in the present study. These results suggest that the higher dose of RB had a significant toxic effect on the developmental patterns of behavior in newborn mice, particularly on the development of motor coordination.

With regard to the avoidance-learning task, it is of considerable interest that mouse offspring exposed to RB at both high and low doses during both early and mid organogenesis showed impaired learning ability. Generally, learning ability is a very important parameter for assessment of developmental neurotoxicity (Cuomo et al., 1996Go; Riley and Vorhees, 1986Go; Tanimura, 1992Go). In this respect, the most important finding in the present study is that prenatal exposure of mice to RB severely impaired performance in the conditioned avoidance-learning test.

The most important conclusion drawn from the present study is that prenatal exposure of mice to RB at a dose lower than that which causes gross malformations or growth retardation altered neurobehavioral performance in the offspring in the preweaning and postweaning periods. Therefore, the behavioral changes observed here were the results of persistent effects of RB on the fetal nervous system.

Furthermore, the motor developmental interference of RB is greater when RB is administered during mid-organogenesis than when it is administered during early organogenesis. Several studies in addition to this one have demonstrated that mid-organogenesis in mice and rats is a highly sensitive period for some behavioral teratogens (Kihara, 1991Go; Rodier, 1976Go, 1980Go; Rodier et al., 1979Go; Vorhees, 1983Go, 1987Go). Vorhees (1983, 1987) also suggested that mid-organogenesis is the most vulnerable period. Mid-organogenesis, at approximately days 9.5–12.5 in the mouse, is an extremely active phase of neurogenesis for the visual areas, cerebral cortices, basal ganglia and forebrain, and for the thalamic, hypothalamic and limbic regions (Rodier, 1980Go).

At present, we can only speculate about potential mechanisms for the observed effects of RB which produced inhibition of adenosine triphosphatase activities in the mouse brain (Desaiah et al., 1977Go). This toxic action altered brain development, and affected early response development and learning abilities in the offspring of mice exposed to RB during middle pregnancy. Furthermore, RB produced central nervous system malformations (Evans and Harbison, 1977Go; Hayes and Hood, 1976Go; Hood et al., 1973Go; Koshakji et al., 1973Go; Surjono et al., 1985Go; Wilson and Harbison, 1973Go), immunosuppression (Sharma, 1993Go), inhibition of mitochodrial function (Hayes, 1976Go) and deceases of cyclic AMP (Hayes et al., 1978Go), malfunction of DNA-dependent RNA polymerse activity and polysomal disaggregation (Watson and Hayes, 1977Go). Some of the actions of RB mentioned above also are developmentally toxic, including actions resulting in behavioral teratogenicity.

However, further studies are required to test for any behavioral effects of developmental RB exposure in postweanling female mice, behavioral effects in progeny of dams treated during late organogenesis or during the lactation period, neurobiochemical effects of RB, and the mechanisms of the effects of RB on developmental neurotoxicity.


    NOTES
 
1 To whom correspondence should be addressed at 1-3-4-303 Harayamadai, Sakai, Osaka 590-0132, Japan. Fax: +81-722-99-8437. E-mail: kiharata{at}crocus.ocn.ne.jp. Back

2 Professor emeritus. Back


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