Mouse and Rat Studies - Reproductive Changes Linked to PCBs

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Mouse and Rat Studies --- Reproductive Changes Linked to PCBs

Mouse and Rat Studies (21-47)
References

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Study #21

increased liver weight
reduced thymus weight
reduced ventral prostate weight
increased testis and epididymus weights
increased testicular and cauda epidiymal sperms counts (PCB 105)
reduced sperm counts (PCB 126)
different PCB congeners have different effects
study used PCB 105, 126 and 153

Experiments were conducted to investigate effects of in utero and lactational exposure to prototype polychlorinated biphenyls (PCBs) on development of the male reproductive system. Three congeners were tested: PCB 153 (an inducer of phenobarbital-responsive enzymes); PCB 105 (a mixed-type inducer whose major metabolite binds with high affinity to transthyretin); and PCB 126 (an Ah receptor agonist). Pregnant Holtzman rats were dosed orally with PCB 153 (5 mg/kg), PCB 105 (2.5 mg/kg), PCB 126 (0.5 ug/kg), or vehicle (1 mL corn oil/kg) beginning on Gestation Day 6 and continuing daily through weaning. There was little if any detectable overt toxicity among dams or pups. Each congener increased relative liver weight and decreased relative thymus weight in 3- and 9-day old pups. PCB 126 accelerated eye opening, while PCBs 105 and 126 delayed preputial separation. At postnatal day 63, ventral prostate weight was reduced by each PCB, while dorsolateral prostate weight was reduced by PCBs 105 and 126. By postnatal day 161, dorsolateral prostate weight was normal in all treatment groups but ventral prostate weight was still reduced by PCB 126 and especially PCB 105. Testis and epididymis weights and testicular and cauda epididymal sperm counts in PCB 105-exposed rats were increased 10-12% at postnatal day 161, presumably due to transient hypothyroxinemia earlier in development. In contrast, PCB 126 tended to reduce sperm counts. Effects of PCB 105 throughout this study were generally greater than (or distinct from) those of PCB 126 even though the daily dose of PCB 126 was the highest that could be given without substantial pup mortality. Although all effects of PCB 105 would have been detected by examining endpoints known to be affected by 2,3,7,8-tetrachlorodibenzo-p-dioxin, these findings suggest that PCB 105 affects development of the male reproductive system by mechanisms in addition to or independent of Ah receptor agonist activity. (Moore et al, 1998)

Study #22

reduced Vitamin D metabolites, even at the lowest PCB dose
study used a PCB mixture reconstituted according to the congener pattern found in human breast milk.

Previous studies revealed effects of polychlorinated biphenyls (PCBs) and other polyhalogenated hydrocarbons on steroid hormone levels and hormone-dependent functions including behavior. In the present study serum concentrations of the vitamin D(3) metabolites 25-hydroxycholecalciferol (25-D) and 1,25-dihydroxycholecalciferol (1,25-D) were determined in rat dams and offspring after exposure to a PCB mixture that was reconstituted according to the congener pattern found in human breast milk. Unmated females were exposed to diets adulterated with 0; 5; 20; or 40 mg PCBs/kg diet. Exposure started 50 days prior to mating and was terminated at birth. Gestational exposure reduced serum concentrations of 1,25-D in dams in a dose-dependent manner. Concentration of 25-D was also decreased at the time of delivery, but not at weaning. Determination of 1,25-D in offspring at weaning revealed reductions in both high-exposure groups. Levels of 25-D were diminished only at the highest exposure level. Internal PCB concentrations in adipose tissue and brains exhibited a linear relation to dosages in diet. Concentrations of PCBs in brains were similar in dams and offspring at birth, but decreased at the end of lactation in dams. In offspring, values increased during this period because of continued exposure via the milk. In the adipose tissue, PCB levels were much lower in offspring than in dams. To our knowledge, this is the first report of PCB-induced effects on vitamin D(3) metabolites. In dams, reductions were seen even at the lowest exposure level used. Further studies are needed to evaluate the biological significance of these reductions in pregnant dams and possible consequences for the developing offspring. (Lilienthal et al, 2000)

Study #23

PCBs reduce gestation age in women and nonhuman primates
uterine contractions increased with increased PCB doses
study used PCB commercial mixtures Aroclor 1242, 1248 and 1254

PCBs reduce the gestation age of women and nonhuman primates. Aroclors are technical mixtures of PCBs and constitute the major forms of industrial PCBs. In this study we hypothesized that shortened gestation length by PCBs was mediated by stimulation of uterine oscillatory contraction. Longitudinal uterine strips from midgestation rats were mounted in standard muscle baths interfaced with a polygraph. Isometric contractions were recorded during exposure to A1242 (3 to 100 uM), A1248 (3 to 300 uM), and A1254 (3 uM to 1 mM) added cumulatively at 20 min intervals. As a solvent control, equal volumes of dimethyl sulfoxide (DMSO) were used. The frequency of contraction increased in a dose-dependent manner with all three Aroclors. The ED50 of A1242, A1248, and A1254 was 53 uM, 121 uM, and 151 uM, respectively. Even after removal of Aroclors, the frequency of contraction remained stimulated for at least 4 h. In order to determine the relationship between exposure time and uterine contraction, three doses of A1242 were selected (10, 50, and 100 uM) and uterine strips were exposed to each concentration for 60 min. The frequency of uterine contractions increased as the time of exposure increased until 60 min, at which time maximum stimulation was shown. These data show that the stimulation of uterine contraction depends on the dose and the duration of exposure, and that the response is not readily reversible. Also, because the apparent Aroclor potency for stimulation of uterine contraction was A1242 greater than A1248 greater than A1254, the more lightly chlorinated PCBs may have more prominent stimulatory effects on rat uterine oscillatory contraction. (Bae et al, 1996)

Study #24

reduced epididymal weight
reduced ovarian weight
malformations of external genitalia
increased liver weight
suppressed immune system
suppressed body weight gain
increased mortality
permanent hearing loss
study used PCB commercial mixture Aroclor 1254

This study was designed to determine the effects in offspring of long-term low-level maternal exposure to Aroclor 1254 (A1254). Primiparous rats (22-24/dose) received 0, 0.3, 1 or 3 mg/kg A1254 (po) for 13 weeks prior to breeding and throughout gestation and lactation. We assessed offspring at several ages for: serum thyroid hormones; liver weights and PCB concentrations; body weight; mortality; testis, epididymis and male sex accessory gland weights; cauda epididymal sperm counts; ovarian and uterine weights; morphology of external female genitalia; auditory thresholds; and performance of a delayed matching-to-position (DMTP) task. Body weight gain was suppressed by 10%, and mortality increased by 11%, in the high dose group relative to controls. Serum T4 was decreased in a dosage-dependent manner during the preweaning period (maximal decrease of 60% on PND14), with a significant decrease of 21% in the low-dose group. Liver-to-body weight ratios were elevated in the middle- and high-dose groups at all time points prior to weaning. Both T4 and liver weights recovered to control levels by PND70. Epididymal weight was reduced (high dose) in young male rats, but recovered by older ages. Ovarian weight was reduced in the middle and high dose groups in cycling animals and subtle malformations of the external genitalia were also detected. There were no effects on acquisition or performance of the DMTP task. Consistent with previous data, steady-state maternal A1254 exposure caused permanent low-frequency hearing deficits in the high-dose group. These data demonstrate hypothyroxinic, ototoxic, and reproductive effects of long-term steady-state developmental exposures to PCBs. (Crofton et al, 1998)

Study #25

greater metabolism of estradiol hormone
greater metabolism of artificial endocrine disruptor pesticide, Methoxychlor
lower serum levels of estradiol
study used PCB commercial mixture Aroclor 1254

Polychlorinated biphenyls (PCB's) are well known inducers of hepatic cytochrome P450. The influence of gestational and lactational exposures of rats to the PCB mixture Aroclor 1254 was determined for hepatic microsomal metabolism of 17beta-estradiol (E2) and the proestrogenic organochlorine insecticide methoxychlor (MXC). Dams were administered 4 mg/kg/day of Aroclor 1254 in safflower oil p.o. from gestational day 6 to post-natal day (PND) 22 (weaning). Pups were sampled on PND 15, 23, or 31. There was little E2 metabolism in microsomes of controls of either sex at PND 15 or 23, but there was greater metabolism in the PCB-treated animals, with 2-hydroxyestradiol (2-OH-E2) the major metabolite. There was more 2-OH-E2 production in the control microsomes at PND 31 than from the younger ages, and several additional metabolites were observed in the microsomes from PCB-treated animals. Enhanced hepatic metabolism of E2 may have been responsible for lower serum E2 levels observed in PCB-treated prepubertal females. There was greater MXC disappearance and a higher level of appearance of the estrogenic metabolite hydroxyphenyl-trichloroethane (HPTE) as well as other MXC metabolites in hepatic microsomes from the PCB-treated animals compared to the controls in both sexes. In high dose in vivo treatments with MXC, the enhanced uterine weights and depressed testicular weights induced by MXC were attenuated in the animals also treated with PCBs. It appears that MXC is metabolized to non-estrogenic metabolites more quickly in PCB treated animals than in controls. Therefore, PCB exposure is capable of altering the hepatic metabolism of both endogenous estrogens and the pro-estrogen MXC which may influence the response of the developing reproductive system to endogenous or exogenous estrogens. (Chambers et al, 2000)

Study #26

reduced fecundity (fewer offspring)
reduced fertilizing ability in eggs
enlarged livers
thymus atrophy
study used PCB 77

Reproductive disturbances in mammals caused by PCB exposure have been identified in many studies. These disturbances include reduced germ cell numbers and frequencies of implanted ova in mice, small litter sizes and prolonged estrous cycles in mice and rats, and abortion in rhesus monkeys. The objectives of this study were to investigate the effects of 3,3',4,4'-tetrachlorobiphenyl (TCB) on reproduction of female mice and oocyte fertilizing ability in vitro of the offspring. Thirteen-week old female C57BL/6J mice (F-0) were fed with 0, 3, or 30 ppm TCB in lab chow for 2 weeks before mating. The treatment continued through mating, gestation, lactation, and the postnatal development of the offspring (F-1). Fecundity in F-0 females was 83.3, 75.0, and 50.0% in the control, 3, and 30 ppm treated mice, respectively. Females treated with 30 ppm TCB had enlarged livers during pregnancy and lactation. Changes in liver size were less apparent in the 3 ppm treated mice. In vitro fertilizing ability of oocytes from F-1 of the 3 and 30 ppm groups was decreased. At 5 and 6 weeks, liver enlargement and thymus atrophy were apparent in F-1 females exposed to 30 ppm of TCB. (Huang et al, 1994)

Study #27

reduced fecundity (fewer offspring)
reduced survival of offspring
reduced fertilizing ability in eggs
enlarged livers
thymus atrophy
study used PCB 77

This study investigated the effects of 3,3',4,4'-tetrachlorobiphenyl (TCB) on the reproductive capacity of female mice. Female C57BL/6J mice (F-0) were fed diets containing 0, 3, or 30 ppm TCB for 2 weeks before pairing with nontreated C57BL/6J males for a 10-day breeding period. Females were continued on their treatment diet throughout mating, gestation, and lactation. Female offspring (F-1) were fed the same diet as their dams throughout the study. The reproductive capacity of F-1 females was examined by mating with non-treated B6D2-F1 males. In addition, the fertilizing ability of eggs from F-1 females was examined in vitro by insemination with sperm from nontreated B6D2-F1 males. Fecundity in F-0 females after mating was 80%, 71%, and 47% in the 0, 3, and 30 ppm treatment groups, respectively. Four-day and 21-day survival indices were lower for offspring of 30 ppm TCB-treated F-0 females than for offspring of the control females. Fecundity in F-1 females was the same among all treatment groups, however, all offspring born to 3- and 30-ppm TCB-treated F-1 females died before 4 days of age. Although the litter size at birth was not affected, the in vitro fertilizing ability of eggs in the 3- and 30-ppm treatment groups was lower than in the control group. This decrease in fertilizing ability was associated with an increase in degenerated eggs. F-0 females treated with 30 ppm TCB had enlarged livers during pregnancy and lactation. At 5 and 6 weeks, liver enlargement and thymus atrophy were apparent in F-1 females exposed to 30 ppm TCB. This study demonstrated impaired reproductive capacity and

decreased egg fertilizing ability in TCB-treated female mice. (Huang et al, 1998)

Study #28

increased testis weights
decreased sperm motility
decreased sperm fertilizing ability
weight changes
study used PCB 77

The objectives of this study were to investigate the effects of 3,3',4,4'-tetrachlorobiphenyl (TCB) on reproductive performance and sperm fertilizing ability in male mice. C57BL/6J female mice (F-0) were treated with 0, 3 ppm, and 30 ppm TCB two weeks before breeding. Each female was then paired with a non-treated male for 10 days. Treatments continued through mating, gestation, and lactation. Male offspring (F-1) were given the same diet as their dams throughout this study. F-1 males at 7, 17, and 60 weeks of age were paired with non-treated females. Body weights, litter sizes, sex ratios, and survival indices of offspring sired by F-1 males were recorded. Sperm fertilizing ability in vitro was examined with eggs collected from nontreated females when F-1 males were at 9 and 19 weeks of age. Sperm motion analysis was performed with a computer-assisted program hourly after epididymal sperm were collected. Increased testis weights were observed in the 30 ppm-treated weanlings, but not in pubertal and mature mice. Results of sperm motion analysis for F-1 males were the same among all treatment groups, except for decreased sperm motility observed in 9-week-old 30 ppm-treated males 2.5 hours after collection. The percentage of eggs fertilized in vitro by sperm from 30 ppm-treated F-1 males at 19 weeks of age decreased, but not at 9 weeks of age. Increased mortality was observed in offspring sired by 3 ppm- and 30 ppm-treated F-1 males only at 60 weeks of age, but not at 7 and 17 weeks of age. Increased body weights were observed in offspring of 30 ppm-treated F-1 males at 17 weeks of age, but not at 7 and 60 weeks of age. Reproductive performance and sperm fertilizing ability in vitro were impaired by TCB exposure. (Huang et al, 1996)

Study #29

reduced sperm fertilizing ability
increased testis weights
study used PCB 77

This study investigated the effects of 3,3',4,4'-tetrachlorobiphenyl (TCB) on the reproductive performance and in vitro sperm fertilizing ability of male mice. C57BL/6J female mice (F-0) were fed diets containing 0, 3, or 30 ppm TCB for 2 weeks before pairing with nontreated males for a 10-day breeding period. Females were continued on their treatment diet throughout mating, gestation, and lactation. Male offspring (F-1) were given the same diet as their dams throughout this study. F-1 males at 7 and 17 weeks of age were mated to nontreated B6D2-F1 female mice. Body weight, litter size, and survival indices of offspring sired by F-1 males were recorded. Sperm fertilizing ability of F-1 males at 9 and 19 weeks of age was examined in vitro using eggs collected from nontreated B6D2-F1 females. Sperm motion analysis was performed at the same time. When 7- and 17-week-old F-1 males were mated to nontreated females, no differences in fecundity, litter size, sex ratio, or survival indices among any of the treatments were observed. However, sperm fertilizing ability of 30 ppm-treated F-1 males at 19 weeks of age was less than that of the control mice. Testes weights were greater in 3-week-old, 30 ppm-treated mice. (Huang et al, 1998)

Study #30

temporary effect on germ cell numbers in males
increased number of eggs and follicles in females
enhanced productivity in females
study used PCB 77

Female mice from the C57/B1- and CBA/S-strain, respectively, were administered 3,3'4,4'-tetrachlorobiphenyl once a week for two weeks prior to mating, during mating, gestation and lactation, altogether at seven weekly occasions. The orally administered amounts were 9 or 15 mg/kg b.wt. per occasion. Male and female offspring (F1), exposed in utero were collected for histological analysis of the testes and ovaries. Other C57/B1-females (F1) were tested for their reproductive capacity. In the C57/B1-males tetrachlorobiphenyl only had a temporary effect on germ cell numbers, and spermatogenesis was normal again at 56 days after birth. In the ovaries 28 days after birth, an increased number of oocytes and follicles were observed, the effect being more pronounced in the C57/B1-strain. The reproductive capacity expressed as mean litter size seemed not to be affected by the histologically observed changes. Concerning the number of litters per female there were indications of an enhanced productivity in tetrachlorobiphenyl-exposed F1-females. Malformations of any kind were not observed. (Ronnback et al, 1994)

Study #31

decrease in implanted eggs
decrease in the number of young per litter

The reproductive capacity of mice nursed by mothers given DDT or polychlorinated biphenyls (PCBs) was assessed through the frequency of implanted ova. On the day of parturition female mice were given 50 milligrams per kilogram (mg/kg) DDT, 50mg/kg PCBs or a corresponding amount of vehicle alone. Injections were repeated once a week for 3 successive weeks. When offspring nursed by these females reached sexual maturity they were mated. On day 14 of gestation females were killed and the number of corpora lutea, placentas and fetuses were counted. Some offspring were mated with untreated controls. If only one of the pair had been nursed by a mother treated with either DDT or the PCBs there were no significant decreases in frequency of implanted ova. If both animals were suckled with milk from these mothers there was a significant decrease in implanted ova. If both were given DDT implanted ova decreased to 79 percent. If the mothers received PCBs the implanted ova decreased to 75 percent. No significant differences were seen between control and experimental groups in the number of resorptions. The authors conclude that even small doses of PCBs or DDT can cause a decrease in the number of young per litter in mice. Possibly these compounds disturb normal sexual development by increasing the catabolism of steroids during the lactation period. (Kihlstrom et al, 1975)

Study #32

inhibited in-vitro egg fertilization
inhibited embryo development
study used PCB commercial mixture Aroclor 1254

The reproductive toxicity of aroclor-1254 in B6D2F1-mice was studied in-vitro. Cumulus masses of oocytes collected from female mice were placed in culture medium containing 0.01, 0.1, 1.0, or 10.0 micrograms per milliliter (microg/ml) aroclor-1254 to which epididymal sperm suspensions obtained from male mice, not exposed to aroclor-1254, were added. The effects on in-vitro oocyte fertilization (IVF) were assessed by determining the percentage of fertilized ova 20 to 24 hours later. A similar experiment was performed in which the oocytes were preincubated for 6 hr with 0, 0.01, 0.1, 1, or 10microg/ml aroclor-1254 before addition of the sperm suspensions. Sperm obtained from male mice were incubated with 0, 0.01, 0.1, 1.0, or 10.0microg/ml aroclor-1254. They were added to untreated oocyte cultures. The effects on IVF were determined as before. Sperm suspensions from male mice were incubated with 0, 1.0, or 10.0 microg/ml aroclor-1254 for 15, 45, or 90 minutes. The effects on sperm motility were determined. Two cell stage embryos obtained from superovulated pregnant mice were incubated with 0, 0.01, 1.0, or 10.0microg/ml aroclor-1254 for up to 96 hours. The effects on embryo development were assessed by determining the proportion of embryos consisting of at least four cells at 48 hours and the proportion of expanded blastocysts at 96 hours. All concentrations of aroclor-1254 significantly inhibited IVF when treated oocytes were mixed with untreated sperm. IVF was not affected when untreated oocytes were mixed with aroclor-1254 exposed spermatocytes. Aroclor-1254 did not significantly affect spermatocyte motility. Aroclor-1254 significantly inhibited embryo development after both 48 and 96 hours. The authors conclude that aroclor-1254 has adverse effects on oocytes, IVF, and embryo development in mice. (Kholkute et al, 1994)

Study #33

lower birth weights
reduced number of offspring
reduced survival of offspring
pronounced reproductive effects in mammals, even at low PCB levels
effects are amplified through multigenerational exposure
study used PCB commercial mixture Aroclor 1254

A multigenerational study of the effects of chronic dietary polychlorinated biphenyl (PCB) exposure on reproduction and growth was conducted in oldfield-mice. Mated pairs of Peromyscus-polionotus-mice were fed diets containing 0 or 5mg/kg Aroclor-1254 (11097691) for 12 months. A total of 30 breeding pairs from the F1 generation were established and maintained on the same PCB feeding protocol for 12 months. This process was repeated for the F2 generation. The number of litters born and litter size were recorded for the F1 and F2 generations. Birth weights of the neonatal mice were recorded. Survival of the F1 and F2 weanlings was determined. All mice in each generation were killed after 12 months to determine the body burden of Aroclor-1254. Carcasses were processed and analyzed for PCB levels by gas chromatography with electron capture detection. No treatment related effects were seen in the parental generation. Mean birthweights of PCB exposed F1 neonates were significantly lower than those of the controls and the parental generation. The number of offspring born per month relative to the number of months of mating was significantly decreased relative to the controls. The percentage of offspring surviving to weaning was significantly decreased relative to the F1 controls. The decreases in number of litters born per month, litter size, birth weight, and number of offspring surviving to weaning were more pronounced in third generation exposed mice than in the second generation of exposed mice. The mean PCB body burdens in the parental and first generation controls were 0.31 microgram/gram (microg/g). The mean PCB body burdens in the exposed parental, F1, and F2 generations were 3.28, 7.51, and 14.69microg/g, respectively. The authors conclude that PCBs have pronounced reproductive effects in mammals even at the low level of exposure, and such effects are amplified through multigenerational exposure. (McCoy et al, 1995)

Study #34

fewer pregnancies
fewer fetuses
reduced egg implants
higher resorption rates of embryos
reduced ventral prostate weight
fewer alveoli, less mucosal folding and flattened epithelial cells in the alveoli of the prostate
PCBs were persistent in the bodies, 20 weeks after PCB feeding stopped
less weight gain during growth
hair loss, weight loss, swollen abdomen and death in 5 of the high dose group
study used PCB commercial mixture Aroclor 1254

Effects of the early administration of polychlorinated biphenyls (PCBs) on adult fertility and the condition of sexual accessory glands in males were investigated using sperm positive pregnant rats. The PCB Aroclor-1254 was administered by oral intubation to lactating dams on days one through three, five, seven, and nine postpartum. Treatment groups received 0, 8, 32, or 64mg/kg doses. Male offspring were autopsied at 165 days of age, at least 8 days after mating. The average number of fetuses was significantly less and the average number of implantations was reduced among normal virgin females mated to male offspring exposed to the two higher dose levels of PCBs. Resorption rate among these females was also higher and fewer of them became pregnant after exposure to males. Ventral prostate weights in all experimental male offspring were significantly less than those of controls. Fewer numbers of alveoli, less folding of the mucosa, and flattened epithelial cells in the alveoli were noted on microscopical examination of these glands. PCB residues were found in both liver and adipose tissue of all experimental offspring, even though they had not received PCBs since weaning, a period of about 20 weeks. Weight gain in litters exposed to the two higher dose levels was significantly less during days one through 11 of lactation, but subsequent weight gain was normal. Five offspring of the highest dose level group developed a toxic syndrome characterized by loss of hair, weight loss, and a swollen abdomen, culminating in death. The author concludes that early exposure to PCBs results in damage to the reproductive system in these animals. (Sager, 1983)

Study #35

delayed vaginal opening and first estrus (delayed puberty)
reduced uterine weight
decreased uterine response
impairment of fertility
irregular cycle patterns
reproductive aging may be delayed
study used PCB commercial mixture Aroclor 1254

The effects of translactational exposure to a polychlorinated biphenyl (PCB) mixture, Aroclor-1254 (11097691) on puberty, estrous cycles, fertility, and uterine response in rats at three different ages were studied. Sperm positive Holtzman-rats were obtained on day one of pregnancy and observed daily until parturition. The dams were given oral treatments on days one, three, five, seven and nine of lactation at doses of 8, 32, or 64 micrograms/gram in peanut-oil. At the two higher doses, the vaginal opening and first estrus were each delayed. A pronounced and consistent effect on uterine response was noted at all exposure levels. Uterine wet weights were reduced at all stages of the estrous cycle in the mature adults at the higher dose levels. Offspring of the lower dosed group exhibited a decreased uterine weight in proestrus and in light induced persistent vaginal estrus (PVE). Exogenous estradiol-17-beta given to ovariectomized offspring was less effective in causing a uterotrophic and vaginal response in all the offspring exposed to PCBs. Analysis of estrous cycles for 40 days at all ages indicated increases in diestrus. Young adults of the highest dose group exhibited less success with preimplantation stages. Mature adults at the two highest dose levels showed an effect at preimplantation and/or postimplantation stages. Exposure to PCBs did not hasten reproductive aging at any of the ages examined. The authors conclude that translactational exposure to a PCB mixture that has little notable effect on the dams not only delays puberty in the female offspring, but also several months later results in decreased uterine response, impairment of fertility, and irregular cycle patterns. Reproductive aging, however, is not hastened, and may even be delayed. They note that many of these effects could be explained in part by interference with estrogen. (Sager et al, 1994)

Study #36

feminization of mixed function oxidation and glucoronidation in adult males
irreversible effects

An evaluation was made of the role of metabolic activation and deactivation reactions during perinatal development in relation to developmental pharmacology and toxicology. The mixed function oxidases, epoxide hydration and conjugation enzyme systems were evaluated. Placental transfer and milk secretion of chemicals were discussed in relation to maternal, placental, and fetal metabolism. Two ways of modifying normal patterns of enzyme development were discussed: enzyme induction and enzyme imprinting. Newborn exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in milk was shown to be the primary cause of postnatal induction of the mixed function oxidases and glucuronyl-transferase following treatment of pregnant rats with TCDD. For the perinatal induction of hepatic enzymes by pure polychlorinated biphenyls (PCBs), structure activity relationships were defined. Two classes of PCBs were described: cytochrome-P-450 inducers and cytochrome-P-448 inducers. The sexual differentiation of enzyme activity was demonstrated as controlling the imprinting or programming of hepatic metabolism. In prepubertal animals the male and female activities were similar. In adult animals, pronounced sex differences were evident. A feminization of mixed function oxidation and glucuronidation in adult males resulted from the treatment of newborn rats with hormonally active agents. Immature males or females or adult females demonstrate no changes following this treatment. The effect was irreversible and was under control of the pituitary/hypothalamic/gonadal system components. Neonatal exposure to hormonally active chemicals also feminized the hepatic response to cadmium in the animals as adults. (Lucier, 1979)

Study #37

enzyme induction
behavioral and kidney abnormalities
alteration of normal imprinting of sexual differentiation --- feminization
study used PCBs 77 and 153

Our studies were designed to define structure-activity relationships for the effects of pure PCB congeners and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on hepatic enzyme development. The organohalogens were usually administered to pregnant rats and enzyme activities measured in fetuses and offspring (6, 20, and 55 days after birth). Offspring of pregnant rats exposed to TCDD had elevated levels of benzpyrene hydroxylase and nonsteroid UDP glucuronyltransferase (UDPGT). Postnatal inductive actions of TCDD were caused primarily by newborn exposure to TCDD in milk. 3,4-3',4'-Tetrachlorobiphenyl (4-CB) induced P448-dependent enzymes in 6- and 20 day-old rats whereas 2,4,5-2',4',5'-hexachlorobiphenyl (6-CB) induced P450-dependent enzymes. 4-CB was a potent teratogen (behavioral and kidney abnormalities) but 6-CB produced no such developmental defects. 4-CB might also alter the normal imprinting of sexual differentiation of hepatic metabolism as evidenced by a feminization (decrease) of UDPGT in adult ma (incomplete abstract) (Lucier, 1979)

Study #38

reduced seminal vesicle weight

The effects of p,p'-DDT or PCB (polychlorinated biphenyls) on the hepatic cytochrome P-450 contents and on the weights of androgen dependent male sex organs in intact and castrated testosterone treated male mice have been studied. The results obtained show that hepatic cytochrome P-450 contents are significantly higher in the DDT or PCB treated animals than in the controls; that dry weights of the seminal vesicles in the DDT or PCB treated castrated animals are significantly lower than in the castrated controls, whereas no such difference exists in the intact animals; and that dry weights of the testes in the DDT or PCB treated animals do not differ significantly from those in the controls. (Orberg et al, 1974)

Study #39

no change in testosterone levels
increased testes weight
study used PCB 153

Male mice were exposed to two different preparations of PCBs. The pure congener 2,2',4,4',5,5'-hexachlorobiphenyl (6-CB) was given at daily doses of 4, 20, and 40 mg/kg b.wt. during the perinatal or pubertal period. A technical mixture of PCB (Clophen A50) was administered during puberty at daily doses of 8, 40, 80, 120, and 160 mg/kg b.wt. Treatments were, in the different experiments, carried out every second or third day for three to five weeks. Treatment during puberty was started when the mice were 5 weeks old. The perinatal exposure was started on day 13 of gestation and ended on day 24 post partum. There were no significant differences in the plasma levels of testosterone between the treated mice and the controls after any of the treatments, but there was an increase in the relative testes weights for the animals treated perinatally. No influence on the biosynthesis of testosterone in the testicular interstitial cells in vitro could be demonstrated. (Johansson, 1987)

Study #40

increase in acid phosphatase activity in the interstitial tissue
no significant chromosomal damage
no arrest of spermatogenesis
no changes in testes or epididymis
study used PCB commercial mixture Aroclor 1254

Adult male Sprague-Dawley rats (36) were given by stomach tube either corn oil alone or daily doses of Aroclor 1254 (50 mg/kg) in corn oil for 7 days. The rats were killed at 24 h, 7, 15 and 30 days. Cytogenetic analysis and histochemical and histopathological studies of the testicular tissues indicated that Aroclor 1254 caused no significant chromosomal damage and did not arrest the rate of spermatogenesis in the male rat. Observations revealed no alterations in the testes or epididymis of the treated rats, though an increase was observed in acid phosphatase activity of the interstitial tissue. (Dikshith et al, 1975)

Study #41

decreased serum androgen levels
reduced androgen production in testes
reduced ability to convert key hormones to testosterone
study used PCB commercial mixture Aroclor 1248

Polychlorinated biphenyls (PCBs) are complex mixtures of congeners that exhibit carcinogenic and toxicant activities in a variety of mammalian tissues. Here, we studied the acute in vivo and in vitro effects of a commercially used PCB product, Aroclor 1248 (A1248), a mixture of tri-, tetra-, and pentachloro congeners. Single intraperitoneal (i.p.) or bilateral intratesticular (i.t.) injections of A1248 decreased serum androgen levels in both groups 24 h after injection. Chorionic gonadotropin-stimulated androgen production by acute testicular cultures from both groups was also reduced, and progesterone production was attenuated in cultures from i.t.-treated animals. The capacity of the postmitochondrial fractions from testes of i.t.-treated animals to convert pregnenolone to progesterone and progesterone to testosterone was reduced as well. In vitro studies revealed that a 10- to 15-min exposure of postmitochondrial testicular fractions and intact interstitial cells from normal animals to A1248 in a subnanomolar concentration range was sufficient to attenuate the conversion of pregnenolone to progesterone and progesterone to testosterone. At micromolar concentrations, A1248 added in vitro also inhibited the conversion of Delta(4)-androstendione to testosterone without affecting the viability of interstitial cells. These results indicate that A1248 down-regulates the testicular androgenesis by an acute inhibition of 3beta-hydroxysteroid dehydrogenase, 17alpha-hydroxylase/lyase, and 17beta-hydroxysteroid dehydrogenase activities. (Andric et al, 2000)

Study #42

reduced plasma steriod concentrations
reduced erythropoiesis
study used PCB commercial mixture Aroclor 1254

Alterations in erythropoiesis induced by exposure to a polychlorinated biphenyl (1336363) (PCB) was studied in rats. Male Sprague-Dawley-rats were injected intraperitoneally with 0, 10, 20, and 40mg/kg Aroclor-1254 (11097691) in a 0.1 milliliter (ml) volume of sesame oil. After 15 days, they were killed, and three 1.0 ml blood samples were obtained from each animal. The average number of red blood cells was reduced by Aroclor-1254 in a dose dependent manner from 9.21 x 10(6) to 7.31 x 10(6) erythrocytes per cubic centimeter (controls and 40mg/kg groups, respectively). The authors interpret their results based on the findings of an earlier study in which androgen specific tissues, such as the testes and accessory glands, were reduced in weight under the influence of phenobarbital by way of hydroxylation of testosterone. Aroclor-1254 has been shown to induce hepatic microsomal enzymes which have the ability to hydroxylate natural steroid hormones, with increased excretion of these polar metabolites reducing plasma steroid concentrations. The authors consider that the same mechanism operated to reduce steroid levels and erythropoiesis in their experiments. (Derr, 1979)

Study #43

reduced litter size
decreaed litter survival
increased mortality
decreased adult mating performances
increased liver weight
less weight gain
increased testes to body weight ratios
reduced hemoglobin
reduced hematocrits
study used PCB commercial mixtures Aroclor 1254 and Aroclor 1260

The effects of polychlorinated-biphenyls (PCB) on reproduction were studied in rats. The oral median lethal dose (LD50) was determined for Aroclor-1254 and for Aroclor-1260 in male weanling Sherman-rats. The intravenous LD50 was determined for adult female rats. For two generation reproduction studies, rats were fed doses up to 100 parts per million (ppm) Aroclor-1254 or Aroclor-1260. The rats were mated at 3 and 7 months to produce F1a and F1b generations, respectively. F1a and F1b rats were mated at 3 and 8 months to produce F2a and F2b generations, respectively. F1a rats were fed the PCB diet from week 3 to 4; F1b rats were fed the diet after weaning. Exposure was continuous through mating, gestation, and lactation until death. Weights were recorded at several intervals. Viability counts were made. Litters were inspected. Hematology was performed; rats were then sacrificed and organs were weighed. One generation studies were performed on rats with up to 500ppm PCBs. Single dose LD50 was 1,295 milligrams per kilogram (mg/kg) and 1,315mg/kg for Aroclor-1254 and Aroclor-1260, respectively. Intravenous LD50 was 358mg/kg. The 500ppm Aroclor-1260 reduced litter size and decreased litter survival. Mortality in F1b offspring increased with 100ppm Aroclor-1254; adult mating performances markedly decreased. Liver weight in some 21 day weanlings exposed to either PCB increased. F1b females given 100ppm Aroclor-1254 gained less weight than controls. At 100ppm, Aroclor-1254 exposed F1b males had significantly increased testes to body weight ratios and significantly reduced hemoglobin; female F1b adults had significantly reduced hemoglobin and hematocrits. There were no reproductive effects in rats fed 5 to 100ppm Aroclor-1260 through two generations. The authors conclude that some commercial PCB mixtures alter reproductive processes in animals. (Linder, 1974)

Study #44

reduce testes weights
death of seminiferous tubules
disappearance of spermatogonial cells
hypertrophy of interstitium between the tubules
increased liver weight and numerous liver changes
study used PCB commercial mixture Kanechlor 500

The effects of a polychlorinated biphenyl (PCB) and laurylbenzene-sulfonic-acid-sodium-salt (ABS) were studied in rats. Male Wistar-rats were administered diets containing 0, 10, 100, or 500 parts per million (ppm) Kanechlor-500, a Japanese manufactured PCB mixture, plus tap water containing 0 or 1,000ppm ABS for up to 7 months. Selected animals were killed at 1, 3, or 7 months, the liver and testes were removed and weighed, and examined for histopathological changes. Hepatic RNA, DNA, and protein content, and selected biochemical parameters were determined. In animals given PCB or PCB plus ABS, liver weight was increased significantly. In animals given only ABS, liver weights were normal. Rats given PCB or PCB plus ABS showed swelling of individual cells, picnotic nuclei, cytoplasm with many vacuoles, and degenerative changes in scattered areas of the liver. Testicle weights were decreased in animals given PCB plus ABS only after 7 months. Histological changes included necrosis of the seminiferous tubules, disappearance of spermatogonial cells, and hypertrophy of the interstitium between the tubules. Liver DNA was decreased in rats given PCB or PCB plus ABS; however total DNA content underwent no significant change due to increase in liver weights. Total RNA and protein content per liver increased significantly in proportion to the increase in liver weight. Kanechlor-500 alone or given in combination with ABS significantly increased liver cholesterol and aniline-hydroxylase activity and decreased sodium/potassium/magnesium dependent adenosine-triphosphatase activity. PCB or PCB plus ABS caused significant increases in serum glutamic-oxaloacetic-transaminase and serum glutamic-pyruvic-transaminase activities after 3 and 7 months. The authors note that the effects of PCB or PCB plus ABS on the reproductive physiology of male rats are significant and should be investigated further. (Itokawa et al, 1975)

Study #45

reduced testicular sperm concentrations
reduction in pentobartital-induced sleeping times --- intensified by feed restriction
increased adrenal gland weights
increased liver weights
increased plasma corticoid concentrations --- intensified by feed restriction
study used PCB commercial mixture Aroclor 1254

Aroclor 1254, a polychlorinated biphenyl (PCB), was fed to adult male white mice in an ad lib diet at levels of 50 and 200 ppm and in a restricted diet (50% of the amount consumed ad lib) at levels of 100 and 400 ppm to compare effects and possible interactions of PCB ingestion and feed restriction on select endocrine and reproductive characteristics and barbiturate-induced sleeping times. The mice were maintained on the 2 nutritional levels for 30 days, whereas the PCB was incorporated into the diets during the final 15 days only. PCB ingestion significantly increased paired adrenal gland weights, liver weights and plasma corticoid concentrations. In addition, PCB-fed mice exhibited reduced testicular spermatozoa concentrations and pentobarbital-induced sleeping times. PCB feeding did not affect final body weights or weights of the reproductive organs. Feed restriction reduced weights of the seminal vesicles, preputial glands, testes and final body weights. Feed restriction increased adrenal weights, pentobarbital-induced sleeping time and plasma corticoid concentrations. Liver weights and testicular spermatozoa concentrations were not affected by feed restriction. The PCB-associated reduction in sleeping time was greater in feed-restricted mice than in mice allowed food ad lib. The effect on plasma corticoid concentrations was greatly intensified in mice subjected to PCBs and feed restriction simultaneously as compared to mice subjected to feed restriction or PCB feeding separately. (Sanders et al, 1977)

Study #46

reduced litter size
increase number of stillborns
increased mortality of offspring
increased incidence of hydronephroism (kidney damage) and cryptorchid testes (undescended testicles)
increased locomotor activity and general restlessness
study used PCB 77, 153 and a brominated compound

The transplacental toxicity of polychlorinated biphenyls and polybrominated biphenyls was studied in mice. Pregnant CD-1-mice were administered 3,4,3',4'-tetrachlorobiphenyl (TCB), 2,4,5,2',4',5'-hexachlorobiphenyl (HCBP), or 2,4,5,2',4',5'-hexabromobiphenyl (HBBP) orally on days 10 to 16 of gestation. Doses ranged from 0.3 to 32 milligrams per kilogram (mg/kg). The animals were observed for signs of toxicity. The dams were killed on day 19 and the number of resorptions and dead fetuses was recorded. The live fetuses were weighed and examined for abnormalities. After reaching sexual maturity, the fertility of male and female offspring was assessed by serial mating and forced breeding techniques, respectively. The offspring were observed for behavioral changes. Selected offspring were killed and examined for histopathological changes. No maternal toxicity was detected. HCBP and HBBP did not cause any significant fetotoxicity or teratogenicity. TCB at 32mg/kg reduced average litter size, increased the number of stillborn offspring, and markedly increased mortality in the offspring. No consistent major skeletal malformations were found, but there was a considerable increase in the incidence of soft tissue anomalies, such as hydronephroism and cryptorchid testes. Body weight was not significantly affected. No significant changes in fertility of males or females were detected. Increased locomotor activity and general restlessness were observed in about half of the treated offspring. No histopathological changes were detected. The authors conclude that TCB is fetotoxic, teratogenic, and neurotoxic in mice. Efforts are underway to characterize structure/activity relationships and to elucidate the mechanisms of fetotoxicity and behavioral teratology. (Lucier et al, 1978)

Study Review #47

abnormal sex differentiation
numerous other effects
study evaluated PCB 169 and several other chemicals

In humans and rodents, exposure to hormonally active chemicals during sex differentiation can produce morphological pseudohermaphrodism (Schardein, 1993; Gray, 1992). For example, hormonally active drugs like DES (estrogenic), Danazol (androgenic), and progestins cause urogenital malformations in the reproductive tracts of humans and rodents. The current discussion will present new information on the effects of toxic chemicals and pesticides that act on reproductive development via novel mechanisms, including germ cell toxicity, antiandrogenicity, and Ah-receptor binding. Information will be presented that describes how exposure during critical stages of life to synthetic chemicals present in our environment, such as benzidine-based dyes, antiandrogenic fungicides, 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), and PCB congener 169, result in abnormal rodent sex differentiation. In rodents, perinatal exposure to fetal germ cell toxicants reduced the reproductive potential of female, and permanently reduced sperm production in male progeny. Phenotypic sex differentiation, however, was unaffected by these germ cell toxicants. In contrast, antiandrogenic drugs and fungicides induced profound alterations in phenotypic sex differentiation. Effects such as hypospadias, ectopic testes, vaginal pouches, agenesis of the ventral prostate, and nipple retention in male rats were observed commonly. Although these antiandrogens induced no permanent effects in female progeny, another class of chemicals, the Ah-receptor mediated toxicants, did reduce fertility in both male and female rat offspring. Cauda epididymal sperm numbers were reduced permanently in TCDD-exposed male rat and hamster progeny, and female progeny displayed malformations of the external genitalia. Other toxicants produced dramatic alterations of sex differentiation (uterus unicornis, agenesis of the vas and epididymis, and undescended testes), via mechanisms that have not been characterized yet. Since these adult/pubertal alterations resulted from gestational and/or neonatal exposures, future studies should include a comprehensive assessment of reproductive function after perinatal exposure because the developing animal is extremely sensitive to toxicants during sex differentiation, and many of the effects are difficult to detect until late in life. (Gray et al, 1996)

Study #48

prospective study --- not complete yet
will study PCBs 52, 105, 126 and 153

Evidence that environmental exposure to polychlorinated biphenyl (PCB) mixtures adversely affects human health is compelling enough that eight epidemiological studies are currently being conducted. Toxicity of PCB mixtures is generally attributed to their coplanar and mono-ortho- chlorinated congeners that bind to the same (Ah) receptor as does 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), and risk of exposure to PCBs is currently measured in terms of how many "TCDD equivalents" are present in the mixtures. However, most PCB congeners do not bind to the Ah receptor; PCB mixtures cause numerous biological responses not mediated by binding to the Ah receptor; and potent Ah receptor agonists constitute only a tiny percentage of all PCBs in environmental samples. The possibility that perinatal exposure to PCB mixtures adversely affects health in adulthood via Ah receptor-independent mechanisms is essentially unexplored. Our hypothesis is that PCB mixtures adversely affect development of the male reproductive, female reproductive, and central nervous systems via at least three Ah receptor-independent mechanisms, and that PCB mixtures do so at occupationally if not environmentally relevant exposure levels. To test this hypothesis, pregnant/lactating rats will be treated daily with prototype congeners that are major constituents of the human PCB body burden: 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), an inducer of phenobarbital-responsive, drug and steroid metabolizing enzymes; 2,2',5,5'-tetrachlorobiphenyl (PCB 52), a congener whose major metabolite is estrogenic; and 2,3,3',4,4'-pentachlorobiphenyl (PCB 105), a congener whose metabolites bind strongly to thyroid hormone-binding proteins. A fourth congener, the Ah receptor agonist 3,3',4,4',5-pentachlorobiphenyl (PCB 126), will serve as a positive control. Effects of these congeners on development of the male reproductive,, female reproductive, and central nervous systems of offspring of treated dams will be determined. Multiple endpoints within each organ system will be evaluated. For males, these include indices of androgenic status, quantitative analysis of spermatogenesis, fertility testing, and observations of masculine sexual behaviors and potential to display feminine sexual behavior. For females, these include plasma l7beta-estradiol concentrations, estrus cycling, fertility testing, and observations of feminine sexual behaviors. Plasma T4, T3, and TSH concentrations will be measured in both sexes during the critical neonatal period when sexual differentiation of the central nervous system occurs, and regional distribution of aromatase activity, estrogen receptors, and androgen receptors in the brain will also be determined. For each congener that adversely affects one or more organ systems, a dose-response experiment will be conducted to determine how sensitive rats are to in utero and lactational exposure to this type of congener. Such results will greatly facilitate the ability (abstract incomplete) (PETERSON, prospective study)

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