PCBs and Reproduction - the Mouse and Rat Studies

Note: Please give page time to load

Back to Reproductive Table of Contents

The Mouse and Rat Studies

Introduction
Summaries of Mouse and Rat Studies:

Sexual Behavior Changes Linked to PCB Exposure

Male Reproductive Organs – PCB Effects

Female Reproductive Organs – PCB Effects

Miscellaneous Findings

Details of Studies

Introduction

The following 47 studies show that PCBs can cause a variety of reproductive and sexual changes in laboratory mice and rats. Keep in mind that not all studies are equal in size or quality, though all were published in peer-reviewed scientific journals. The individual researchers often examined only one or two types of effects in one study. No one study covered all possible effects. In addition, many of the studies were conducted with only a few specific types of PCBs (congeners) or limited PCB mixtures, and the health effects varied between types of PCBs, which accounts for some of the conflicting findings listed below. In addition, researchers found that some PCB health effects were triggered by a single PCB dose on one particular day of the pregnancy, and the timing and size of the dose mattered. Many of these PCB health effects appeared in the second or third generation, after exposure of the mother to PCBs. This is not a complete list of all such research, only a sample. For additional study results, visit the TOXNET databases.

Sexual Behavior Changes Linked to PCB Exposure

(each item is one study unless noted)

changes in sexual behavior, especially in males (6 studies)
reduced male and female mating behavior (3 studies)
alteration of normal imprinting of sexual differentiation --- behavioral feminization (3 studies)
behavioral feminization of males --- dose-dependent increase in saccharin preference (2 studies)
dose-dependent and long-lasting alterations of sex-specific behaviors and sex hormone levels in male rats (2 studies)
demasculinization of males
masculinization of females
decreases in saccharin preference in females (a male trait)
preference for the testosterone-paired side in adult male rats
feminization of mixed function oxidation and glucoronidation in adult males
increased locomotor activity and general restlessness
different PCBs produce different results
effects are irreversible

Male Reproductive Organs – PCB Effects

(each item is one study result unless noted)

malformations of external genitalia (gonadal defects - sexual organs) (3 studies)
increased incidence of cryptorchid testes (undescended testicles - birth defect)
disappearance of spermatogonial cells (sperm-forming cells)
decreased sperm count (8 studies)
increased sperm count (2 studies)
no change in sperm count
decreased sperm motility
decreased sperm fertilizing ability (2 studies)
decreased epididymal weight (epididymis = sperm maturation site on the testicle) (3 studies)
no changes in testes or epididymis
epididymides changes
reduced testes (testicles) weight (5 studies)
increased testis weights (2 studies)
decrease in testis weight at day 31, but increase at day 70 (2 studies)
reduced seminal vesicles weight (semen producing region of testicles) (3 studies)
death of seminiferous tubules (site of sperm production)
hypertrophy of interstitium between the tubules (death of the material between the seminiferous tubules)
increased prostate size (at background human PCB consumption levels)
induced prostate growth in the absence or presence of testosterone
permanently increased androgen recepter binding activity of the prostate
reduced ventral prostate weights (3 studies)
fewer alveoli, less mucosal folding and flattened epithelial cells in the alveoli of the prostate
increased distance between anus and genitals (2 studies)
reduced ano-genital length in male pups
delayed preputial separation (prepuce = foreskin on penis)
defects in inguinal zone (groin region)
decrease in male pup weight
early puberty
reduced serum testosterone levels --- higher PCB doses created more reduction (4 studies)
reduced ability to convert key hormones to testosterone
no change in testosterone levels
persistent anti-androgenic effects (anti- male hormone)
decreased serum androgen levels
reduced androgen production in testes
PCB 169 is an anti-androgen
effects of PCB 169 bear little resemblance to those of any known anti-androgen.
reduced plasma steriod concentrations
severe effects on reproduction capacity in males and females (4 studies)
pronounced reproductive effects in mammals, even at low PCB levels
effects are amplified through multigenerational exposure
different PCBs produce different results
effects are irreversible

Female Reproductive Organs – PCB Effects

(each item is one study unless noted)

malformations of external genitalia (gonadal defects - sexual organs) (4 studies)
vaginal distortion
closed vaginas
delayed vaginal opening and first estrus (delayed puberty)
decrease in female weight at time of vaginal opening (2 studies)
accelerated time of vaginal opening
early puberty
enlarged clitoris
reduced number of corpora lutea
reduced uterine weight (2 studies)
uterus changes
decreased uterine response
uterine contractions increased with increased PCB doses
multifocal endometrial epithelial hyperplasia (see also Endometriosis)
reduced ovarian weight (2 studies)
ovaria changes
persistent vaginal estrus (persistent period of fertility – normally only seasonal)
irregular cycle patterns
anovulation (no egg production) by 6 months (premature aging of the reproductive system)
reproductive aging may be delayed
only 12.5% of females able to produce offspring
decreased litter size (8 studies)
reduced number of pregnancies (2 studies)
reduced number of viable litters
increased mortality of offspring (8 studies)
reduced fedundity (fewer offspring) (2 studies)
increased number of stillborns
higher resorption rates of embryos
increased gestation period
lower birth weights
decreased pup weight
decrease in implanted eggs (2 studies)
inhibited in-vitro egg fertilization
inhibited embryo development
reduced fertilizing ability in eggs (2 studies)
increased number of eggs and follicles in females
enhanced productivity in females
impairment of fertility
reduced serum testosterone levels in female pups --- dependent on PCB dose
greater metabolism of estradiol hormone
lower serum levels of estradiol
permanent alteration of neuroendocrine function in females due to PCB exposure in the womb
severe effects on reproduction capacity in males and females (4 studies)
pronounced reproductive effects in mammals, even at low PCB levels
effects are amplified through multigenerational exposure
different PCBs produce different results
effects are irreversible

Miscellaneous Findings

(each item is one study unless noted)

increased liver weight and liver changes (8 studies)
suppressed body weight gain (5 studies)
thymus atrophy (3 studies)
the bioaccumulated mix of PCBs typically found in human breast milk is more toxic than the original commercial mixture (Aroclor 1254) produced by manufacturers (2 studies)
some PCBs alter the toxicity of other reproductive toxins (Methoxychlor, etc.) (2 studies)
timing of the PCB dose during pregnancy may affect outcome
a single moderate PCB dose on one critical day in the pregnancy can change the outcome
in several studies which showed effects, PCBs in the animal tissue were near human background levels
changes resulted largely from PCB exposure in the womb, not through breastfeeding
PCBs were persistent in the body 20 weeks after PCB feeding stopped
slight effects on cell proliferation and mammary gland development
reduced Vitamin D metabolites, even at the lowest PCB dose
suppressed immune system
permanent hearing loss
increased adrenal gland weights
hypothyroidism
hair loss, weight loss, swollen abdomen and death in 5 of the high dose group
PCBs induced enzymes
increase in acid phosphatase activity in the interstitial tissue
no significant chromosomal damage
reduced hemoglobin and erythropoiesis (reduced production and maturation of red blood cells) (3 studies)
increased incidence of hydronephroism (birth defect which causes kidney damage) (2 studies) (see also Cleft Palate and Kidney Damage Birth Defects)
reduction in pentobartital-induced sleeping times --- intensified by feed restriction
increased plasma corticoid concentrations --- intensified by feed restriction

The Mouse and Rat Studies

Study #1

increased prostate size (at background human PCB consumption levels)
decreased epididymal weight
increased distance between anus and genitals
induced prostate growth in the absence or presence of testosterone
permanently increased androgen recepter binding activity of the prostate
dosed from day 16 to 18 of pregnancy
study used PCB commercial mix Aroclor 1016

Recently, significant concerns have been placed on the widespread use of chemicals with persistent estrogenic activity for their long-term effects on human health. In this communication, we investigated whether fetal exposure to some of these chemicals at doses consumed by people, has any long-term effect on the reproductive functions of the male offspring. Thus, time-pregnant CD-1 mice were fed diethylstilbestrol (DES), bisphenol A (BPA), and Aroclor (Aroclor 1016) at an average concentration of 100 ng/kg/day, 50 microg/kg/day, and 50 microg/kg/day, respectively, during Days 16-18 of gestation. A high dose of DES (200 microg/kg/day) was also tested to compare the results of the current study with those of others using the high dose only. The offspring were examined at Day 3, Day 21, and Day 60 following birth. We demonstrated that BPA, Aroclor, and the lower dose of DES enhanced anogenital distance, increased prostate size, and decreased epididymal weight. No effect was found on the testicular weight or size. The chemicals also permanently increased androgen receptor (AR) binding activity of the prostate at this dosage. This is the first demonstration that environmental chemicals program AR function permanently at the dosage consumed by the general population. The higher dosage of DES, on the other hand, produced an opposite effect, decreasing prostate weight, prostate AR binding, and anogenital distance, thus confirming the previous reports. To investigate whether the above mentioned effects of the chemicals represent direct or indirect effects, we also tested the effect of the chemicals on prostate development in vitro. Thus fetal urogenital sinus (UGS), isolated at the 17th day of gestation was cultured with the chemicals in the presence and absence of testosterone (10 ng/ml) for 6 days, and prostate growth was monitored by determining the size and branching of the specimen following histology. Results showed that these chemicals induced prostate growth in the presence and absence of testosterone. They also increased androgen-binding activity. Thus, the results of the in vivo studies were reproduced in the in vitro experiments, suggesting a direct effect of these chemicals on the development of fetal reproductive organs. This is the first demonstration that estrogenic chemicals induce reproductive malformation by direct interference with the fetal reproductive organs and not by interfering with the maternal or fetal endocrine system. The chemicals are able to induce malformation even in the absence of fetal testosterone; however, they are more effective in the presence of testosterone. (Gupta, 2000)

Study #2

early puberty
persistent vaginal estrus
anovulation by 6 months (premature aging of the reproductive system)
permanent alteration of neuroendocrine function in females due to PCB exposure in the womb
dosed on days 2 to 3 of pregnancy
study used PCB commercial mixtures Aroclor 1221, 1242, 1254 and 1260

Polychlorinated biphenyls (PCB) were found to contaminate the ecosystem and reach both prenatal and postnatal individuals via the placental circulation and milk, respectively. Some PCB also possess weak estrogenic activity. Experiments were devised to examine the estrogenic activity of Aroclors (Monsanto Co.) and their capacity to induce a permanently altered pattern of neuroendocrine reproductive function in female rats treated only during neonatal development. Aroclor 1221 at a dose of 1000 mug/kg body wt produced significant uterine growth 24 h after treatment in weanling rats. This estrogenic PCB given to pups only on the 2nd and 3rd days of life induced precocious puberty, persistent vaginal estrus (PVE) and anovulation by 6 mo. of age; the latter end points are signs of reproductive aging and do not normally occur in rats until later in life. Aroclors 1242, 1254 and 1260 did not produce a uterotrophic response in weanling rats at the doses tested nor did they induce the PVE syndrome when given to neonates. There is probably an association between the estrogenic activity of a PCB and its effectiveness in altering neuroendocrine differentiation and inducing premature reproductive aging. (Gellert, 1978)

Study #3

altered sexual behavior
demasculinization
masculination
study used PCBs 105, 126, 153

Experiments were conducted to determine effects of in utero and lactational exposure to prototype polychlorinated biphenyl (PCB) congeners on masculine sexual behaviors. 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. The masculine sexual behaviors of one male per litter were evaluated at approximately 75 days of age (young adulthood) in the presence of a receptive female. Rats were observed for the first ejaculatory series and until the next intromission. There were no clear effects on any parameter examined (mount and intromission number; mount, intromission, and ejaculation latencies; post-ejaculatory interval; copulatory rate or copulatory efficiency) at this time. Sexual behaviors were reevaluated at 225 days of age. All rats were sexually active, but not all ejaculated within the 45 minute observation period. PCB 126 again had relatively little effect, while PCB 105 substantially reduced mount and intromission latencies. PCB 153-exposed rats, in contrast, displayed a variety of altered sexual behaviors. Mount number was reduced by more than 50%, copulatory efficiency was nearly doubled, mount latency was reduced, and intromission latency was reduced by 91%. In addition, while 3-4 rats in each of the other treatment groups didn't ejaculate within 45 minutes (10-11 rats/group), all 12 PCB 153-exposed rats ejaculated (average time from introduction of the female: 15 minutes). These results suggest that in utero and lactational exposure to PCB 153 substantially alters brain biochemistry in mature adulthood. They also suggest that PCB mixtures can affect sexual behaviors by at least two mechanisms: demasculinization caused by Ah receptor agonists such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, and enhanced masculinization caused by PCB 153 and possibly other structurally related congeners. (Rudy et al, 1998)

Study #4

reduced testes weight
reduced serum testosterone levels
behavioral feminization
persistent anti-androgenic effects
used commercial Aroclor 1254 PCB mix and a reconstituted PCB mixture designed to mimic the mix of PCB congeners typically found in human breast milk (after the impacts of a human body’s selective PCB uptake and bioconcentration)
the bioaccumulated mix of PCBs typically found in human breast milk is more toxic than the original commercial mixture (Aroclor 1254) produced by manufacturers

Polychlorinated biphenyls (PCBs) are lipophilic [fat-loving, they concentrate in fats] industrial chemicals which are regularly detected in human breast milk, serum, and tissues. They possess hormone-modulating properties, and, when transferred transplacentally to the developing fetus, PCBs have been shown to induce persistent sex-specific neurobehavioral deficits. Interactions of PCBs with sex steroid-modulated neural differentiation could in part account for such effects. To test this hypothesis, female Long-Evans rats were exposed via food containing 40 mg/kg (40 ppm) of either a reconstituted PCB mixture (RM), composed according to the congener-pattern in human breast milk, or the technical PCBmixture Aroclor 1254 (A1254). The exposure period started 50 days prior to mating and was terminated at birth (postnatal day 0: PND 0). Aromatase (CYP 19) activity was determined in hypothalamus/preoptic area (HPOA) brain-sections from newborn male pups. This enzyme converts testosterone (T) to 17beta-estradiol (E(2)) and plays a key role in sexual brain differentiation. Moreover, serum concentrations of T and E(2), physical development, organ weights, exposure levels, and sex-specific behavior were evaluated at different life stages. On PND 0, a reduced aromatase activity was detected in the HPOA of male RM-pups compared to controls. Female RM-weanlings exhibited significantly elevated uterine wet weights on PND 21, which is a marker for estrogenic activity. In the adult stage (PND 170), male offspring with maternal exposure to either PCB mixture showed markedly reduced testes weights and serum testosterone levels, thus demonstrating persistent antiandrogenic effects. On PND 180, male RM-rats exhibited a behavioral feminization in a sweet preference test, suggesting long-lasting changes in neuronal brain organization caused by the perinatally suppressed aromatase activity. The results suggest that maternal exposure to the RM, the pattern of which is similar to the PCB spectrum in human milk, results in more distinct effects on sex steroid-dependent processes and behavior than the technical PCB mixture A1254. PCB levels in brain and adipose tissue of the exposed offspring lay within 1-2 orders of magnitude above background concentrations in humans. Copyright 1999 Academic Press. (Hany et al, 1999)

Study #5

decreases in saccharin preference in females
timing of the PCB dose during pregnancy may affect outcome
study used PCBs 77, 126, or dioxin

Previous studies have shown that 1 ug/kg or less of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) given late in gestation can demasculinize and feminize reproductive behavior of male Holtzman rats. However, it was not known whether coplanar PCBs had similar effects, or whether other sexually dimorphic behaviors were also affected. In this study, we compared the effects of TCDD and coplanar PCBs on various sexually dimorphic behaviors in male and female rats. Sprague-Dawley rats were dosed with 2 or 8 mg/kg/day PCB 77 (3,3',4,4'-tetrachlorobiphenyl), 0.25 or 1.0 ug/kg, PCB 126 (3,3',4,4',5-hexachlorobiphenyl), 0.025 or 0.1 ug/kg TCDD, or corn oil vehicle on gestation days 10-16. No signs of reproductive or developmental toxicity were observed, and anogenital distance, time of vaginal opening and time of preputial separation were not affected by PCB or TCDD exposure. Rough-tumble play behavior was assessed at 25-45 days of age, but no clear changes in the expected male-female differences were observed. There were also no changes in sexual behavior or saccharin preference in the male rats. The failure to replicate the effects of TCDD on male sexual behavior or to find evidence of changes in other sexually dimorphic behaviors in male rats could be due to differences in the timing of exposure, and/or to strain differences. Because the male littermates of these rats showed striking changes in spatial learning (Seo et al., Neurosci. Abs. 20:1661), cognitive function appears to be a more sensitive behavioral endpoint. Sexual behavior of the female rats was not assessed, but the PCB- and TCDD-exposed females showed significant, dose dependent decreases in saccharin preference. The altered saccharin preference implies that sexual differentiation of the CNS may be affected in females and suggests that studies of sexual behavior in female rats would be warranted. (Amin et al, 1995)

Study #6

only 12.5% of females able to produce offspring
reduced male and female mating behavior
aberrant male sexual behavior
study used PCB 169

On day 1 of gestation female sperm-positive Wistar rats received a single dose of 3,4,5,3',4',5'-hexachlorobiphenyl (PCB 169) at levels of 0, 0.2, 0.6 and 1.8 mg/kg bw. They were allowed to normally deliver and raise their litters. The pups were weaned on day 21 post partum, and kept with food and drinking water ad libitum until they were about 14 weeks old. Subsequently they were paired with non-litter mates from the same dose groups for a period of maximally 2 weeks. In the animals of the control, low and mid dose groups, 94% or more of the animals mated; in the 1.8 mg/kg bw group about 40% of the animals mated. The percentage of females producing a litter was 65% or higher, but in the 1.8 mg group only 12.5% of the females (i.e. 33% of the mated females) was able to produce live pups. To exclude the possibility of retarded sexual maturation the reproduction experiment was repeated when the animals were about 1 year old. This time only animals of the control and 1.8 mg group were used, and they were paired with untreated partners: the PCB-males with young adult virgin females, and the PCB-females with males of proven fertility. The mating and pregnancy indices of the control animals were similar to those of the former experiment. The mating indices were 43% for the PCB-males and 14% for the PCB-females, whereas the pregnancy index for both was 0%. During mating aberrant male sexual behaviour was observed. The observations described above are currently further investigated in a cross-fostering study using the same single-isomer PCB at a dose level of 1.8 mg/kg bw. (Waalkens-Berendsen et al, 1993)

Study #7

effects on male and female reproductive capacity
effects on development of reproductive organs
decreased sperm
closed vaginas
decreased litter size
pup mortality
decreased pup weight
single dose on day 1 of pregnancy
study used PCB 118, 126, 153 or furans

A 2-generation study in rats administered with a range of dose levels of 3,3',4,4',5-PnCB (PCB 126), 2,3',4,4',5-PnCB (PCB 118), 2,2',4,4',5,5'-HXCB (PCB 153) and 2,3,4,7,8-PnCDF (furan) on gestation day (GD) 1 was initiated. In these experiments the development of the F1-generation, sexual maturation, effects on reproductive organs and reproductive capacity in combination with several sex-dependent hepatic cytochrome P450 and steroid hormones in the plasma were studied. During lactation of the F0-generation only for PCB 126 effects on the F1-pups were observed such as decreased litter size at birth, pup mortality and decreased pup weight. In the F1-generation the effects of this PCB-congener on parameters concerning male and female reproductive capacity and the development of the reproductive organs were more pronounced when compared to the PCB 118 and the PnCDF groups. Perinatal exposure to PCB 153 up to dose levels which induced some maternal toxicity did not affect the reproductive capacity; only a slight decrease in the number of epididymal sperm was observed and some F1-females with a closed vagina were observed. It is unlikely that hepatic P450 expression is involved in the induction of reproduction failures, for in these studies lifelong alterations in hepatic P450 expression due to perinatal interference of PCBs with the imprinting of the P450 were not accompanied by the occurrence of reproduction failures. Moreover, in studies with PCB-congeners that did induce reproductive effects, P450 induction was not significant. However, of the congeners tested on PND 21 PCB 126 was most potent in induction of CYP1A1 and 1A2 activities and this effect might have played a role in the observed reproductive failures after sexual maturation of the PCB 118-, PCB 126- and PnCDF-exposed animals. (Waalkens-Berendsen et al, 1996)

Study #8

reduced serum testosterone levels
reduced ano-genital length in male pups
increased testis, brain weights, and sperm
decreased seminal vesicle weights
reduced ventral prostate weights
alterations in sexual behavior
hypothyroidism
single dose on day 15 of pregnancy
study used PCBs 77 and 126

Pregnant Wistar rats were treated orally with a single dose of 100 microg 3,3',4,4'-tetrachlorobiphenyl (PCB 77)/kg b.w. or 10 microg 3,3',4,4',5 pentachlorobiphenyl (PCB 126)/kg b.w. on day 15 of pregnancy. The control rats received peanut oil at the same day. Developmental landmarks were assessed in all offspring rats and reproductive effects of PCB 77 and PCB 126 on male offspring were studied on postnatal day 65 (at puberty) and on postnatal day 140 (at adulthood). The ano-genital distance as well as the ratio ano-genital distance to body length was reduced in male pups of the PCB 126 group and the age at vaginal opening was significantly delayed in the female pups. Testis, brain weights and daily sperm production were permanently increased and seminal vesicle weights were decreased in male offspring of the PCB 77 group. In male rats of PCB 126 group, the brain weights were permanently increased and ventral prostate weights permanently reduced. In both PCB groups, however, serum testosterone concentration was reduced only at adulthood. Additionally, the male rats of the PCB 126 group showed alterations in sexual behavior. In these rats the number of mounts with intromissions was significantly increased. The results of this study show that PCB 126 elicits some TCDD-like reproductive effects after in utero exposure, while the reproductive effects of in utero exposure to PCB 77 on male offspring may be attributed to the neonatal hypothyroidism induced by the substance during early fetal development. Further studies using multiple doses and providing thyroid hormone data will be necessary to support this hypothesis. (Faqi, 1998)

Study #9

severe effects on reproduction capacity in males and females
changes in sexual behavior, especially in males
study used PCB 169

Groups of rats were administered different doses of the coplanar 3,4,5,3',4',5'-hexachlorobiphenyl (PCB 169) or vehicle on day 1 of gestation. Slight maternal toxicity was evidenced by temporarily reduced body weight and food intake of the highest dose groups. The effects observed on physical development of the offspring were minimal. In contrast, severe effects were observed on the reproduction capacity in the highest dose group in both males and females, either when male and female offspring was paired within the same dose group or when they were paired with untreated partners. In addition, indications of changes in sexual behavior were observed, especially in males. (Smits-van Prooije et al, 1993)

Study #10

vaginal distortion
reduced body weight
delayed preputial separation
changed precoital time
changed fecundity rate
reduced litter size
study used PCBs 118, 126, 153, 169, or furans

The effects of 5 different polyhalogenated aromatic hydrocarbons were examined in 2-generation reproduction studies: polychlorobiphenyl (PCB) #118, PCB#126, PCB#153, PCB#169 and 2,3,4,7,8-pentadibenzofuran (PnCDF) (furan) were administered to mated albino Wistar rats on day 1 of gestation. The highest dose levels were chosen as to inflict minor or no maternal toxicity. The planar hydrocarbons (PCB#118, #126, #169 and PnCDF) were expected to produce dioxin-like effects, due to their structure-function relationship. The di-ortho PCB#153, commonly detected in humans, was examined to ascertain the effects of a non-planar PCB in a similar study. The general health and development of the progeny, that was exposed both in utero and during lactation, was recorded at regular time points; few effects were observed. PCB#126 and #169 resulted in consistently reduced body weights; preputial separation in the males exposed to PCB#118 and #126 was delayed, and vaginal distortions were found around the time of sexual maturation in the females in all groups except for those exposed to PCB#153. Once sexually mature, the animals were mated to untreated partners. Mating in itself was successful for all groups and sexes. Precoital time and fecundity rate, however, were changed in the females of all groups and in the males exposed to PCB#126 and #169. Litter size of the females in these latter groups was reduced. (Smits-van Prooije et al, 1995)

Study #11

PCBs in tissue were near human background levels
males feminized in sweet preference behavior
reduced testosterone --- higher PCB doses created more reduction
long-lasting and dose-dependent alterations in sex-specific behaviors
used a reconstituted PCB mixture designed to mimic the mix of PCB congeners typically found in human breast milk (after the impacts of a human body’s selective PCB uptake and bioconcentration)

The aim of the present investigation was to examine the dose-response relationship of maternal exposure to polychlorinated biphenyls on sex-specific behavioral tasks as well as on sex hormone levels in serum. Female Long-Evans rats were exposed via food containing 0, 5, 20 or 40 ug/g of a reconstituted PCB mixture (Co, RM 5, 20, 40), composed according to the congener pattern found in human breast milk. The exposure period started 50 days prior to mating and was terminated at birth (postnatal day 0 = PND 0). PCB exposure levels were determined in brain and adipose tissue on PND 0 and 21. In addition, serum levels of sex hormones were measured in different life stages. Starting on PND 110, sex-specific sweet preference behavior was examined in male and female offspring. About PND 160, male rats were tested for conditioned place preference (CPP) with testosterone as stimulus. Male PCB-treated rats were feminized in their sweet preference behavior. This effect was dose-dependent and affirms previous results. CPP revealed a preference for the testosterone-paired side in rats from the RM 40-group, thus demonstrating greater affective properties of the hormone in these rats. The behavioral effects were corroborated by serum hormone levels. Testosterone was dose-dependently reduced in PCB-exposed rats until late adulthood (PND 310). Tissue concentrations of PCBs were near human background values. Taken together, maternal exposure to a reconstituted PCB-mixture resulted in long-lasting and dose-dependent alterations of sex-specific behaviors and testosterone levels suggesting influences on sexual differentiation in male rats. (Kaya et al, 2000)

Study #12

reduced ejaculated sperm numbers
malformations in females
study used PCB 169 or dioxin

Wildlife from contaminated ecosystems display a variety of reproductive alterations ranging from cryptorchidism to altered social behavior. Concern has arisen that these chemicals can affect humans as well. The formation of valid hypotheses regarding the role of endocrine disrupters on reproduction can be facilitated by mechanistic information from studies using rodents. To this end, we investigated the effects of estrogenic, antiandrogenic and dioxin-like chemicals on sexual differentiation of the rat. At low doses, estrogenic pesticides determine female progeny, while antiandrogenic fungicides demasculinize DNA feminize the male offspring. In utero administration of TCDD (dioxin) or PCB-169 alters reproduction in male offspring, resulting in dramatic reductions in ejaculated sperm numbers and malformations in females. In summary, in utero exposure to estrogenic, antiandrogenic and TCDD-like chemicals produces a profile of effects in the offspring that is pathognomonic for the receptor with which it interacts. (Gray et al, 1996)

Study #13

gonadal defects (sexual organs)
reproductive disorders
study used PCBs 118, 126, 153, or furans

The mechanism behind reproductive effects of 2,3,7,8-TCDD and PCBs after perinatal exposure is still unresolved. Around birth sexual differentiation of hepatic cytochrome P450 expression is achieved. As P450 1A1 (CYP1A1), 1A2 and 2B1 are induced by TCDD and/or PCBs, and also metabolize steroid hormones we hypothesized that: 1) perinatal exposure to PCBs and related compounds might alter hepatic P450 expression permanently; 2) subsequent alterations in hepatic steroid hormone metabolism might be involved in reproduction disorders. Thus, mated female rats were administered a single dose of 2-121 ug 3,3',4,4',5-PnCB (PCB#126) per kg bodyweight, 0.8-81 mg 2,3',4,4',5-PnCB/kg (PCB#118), 19-275 mg 2,2',4,4',5,5'-HxCB/kg (PCB#153) or 0.4-44 ug 2,3,4,7,8-PnCDF/kg (furans) on gestation day 1. Hepatic P450 activity of the pups was measured on postnatal day 21 (PND21) and PND112. At PND21, pups exposed to PCB#126, PCB#118 or PnCDF showed dose-related induction of hepatic EROD (CYP1A1) and MROD (CYP1A2) activities. Whereas, PROD activity (CYP2B1) was induced by PCB#153 and PCB#118. PCB#126 was the most potent congener. At PND112 slight inductions in EROD, MROD and PROD were observed in offspring exposed to PCB#126, PCB#153 or PnCDF. Sex-dependent differences in P450 were found only on PND112. From the highest dose groups male and female pups were selected, raised and tested for reproduction capacity. This offspring showed gonadal defects and reproduction disorders. Potency of the congeners decreased as follows: PCB#126 greater than PnCDF greater than PCB#118. No reproduction effects were observed in PCB#153-exposed offspring. (Bouwman et al, 1996)

Study #14

behavioral feminization of males --- dose-dependent increase in saccharin preference
preference for the testosterone-paired side in adult male rats
reduced serum testosterone levels in female pups and adult male rats --- dependent on PCB dose
dose-dependent and long-lasting alterations of sex-specific behaviors and sex hormone levels in male rats
used a reconstituted PCB mixture designed to mimic the mix of PCB congeners typically found in human breast milk (after the impacts of a human body’s selective PCB uptake and bioconcentration)
the bioaccumulated mix of PCBs typically found in human breast milk is more toxic than an original commercial mixture (Aroclor 1254) produced by manufacturers

Previous work from our group indicated reduced serum testosterone concentrations and feminized saccharin preference in adult male rats and decreased aromatase (CYP19) activity in the hypothalamus of newborn male rat pups maternally exposed to a PCB-mixture which was reconstituted according to the congener pattern found in human breast milk. Effects of the reconstituted mixture were more pronounced than effects of Aroclor 1254. In the present study the dose-response relationship for the reconstituted PCB-mixture was examined. Female rats were fed PCB-loaded diets resulting in an average daily intake of about 0, 0.5, 2 or 4 mg/kg b.wt. Exposure started 50 days prior to mating and was continued throughout mating and gestation until parturition. Adult male, but not female offspring exhibited dose-dependent elevations of saccharin preference indicating a feminization of this sexually dimorphic behavior. Evaluation of conditioned place preference revealed a preference for the testosterone-paired side in adult male rats of the highest exposure group (4 mg/kg b.wt.). In addition, there were dose-dependent reductions in serum testosterone levels in female pups on postnatal day (PND) 21 and in adult male rats. Serum levels of the secosteroid 1.25-(OH)2-vitamin D3, were decreased in dams on 0 and PND 21 and on PND 21 in offspring in a dose-related manner. Taken together, maternal exposure to a reconstituted PCB-mixture resulted in dose-dependent and long-lasting alterations of sex-specific behaviors and sex hormone levels in male rats. (Lilienthal et al, 2000)

Study #15

reduced number of pregnancies
reduced number of viable litters
increased gestation period
liver changes
epididymides changes
uterus changes
ovaria changes
decreased coital time
defects in inguinal zone
reduced testes weight
reduced epididymides and epididymal sperm
reduced seminal vesicles
enlarged clitoris
reduced number of corpora lutea
multifocal endometrial epithelial hyperplasia
changes resulted largely from PCB exposure in the womb, not through breastfeeding
single dose on day 1 of pregnancy
study used PCB 169 (in relatively modest doses)

In the Netherlands, the potential long-term effects of foetal and/or neonatal exposure to PCBs in rats and humans were studied in a collaboration between five institutes. The animal research included studies into the effects of PCBs on metabolism and kinetics, neurology, behavior and fertility of rats exposed to single isomers or commercial mixtures. The present paper describes effects of 2,2',3,3',4,4'-hexachlorobiphenyl (PCB 169) on the fertility, reproduction and early postnatal development of albino Wistar rats. At the start of a 2-generation reproduction study, sperm-positive females were exposed on day 1 of gestation by gavage to a single dose of 0.2, 0.6 or 1.8 mg PCB 169/kg bw dissolved in corn oil, or to corn oil (2 mL/kg bw) only. The offspring (F1-generation) was studied for changes in body weight, general health, development of physical landmarks and several aspects of behaviour. Few of these parameters were affected, but only to a slight extent. The reproduction capacity of the F1-generation animals was also studied, by mating the rats with partners from the same dose group. Only 33% of the mating pairs in the 1.8 mg/kg PCB 169 group produced a viable litter, following an increased duration of gestation. Treatment-related histopathological changes were observed in the liver, epididymides, uterus and ovaria. The same procedures were largely followed in a subsequent cross-fostering study in which initially only two dose groups were formed, vehicle control and 1.8 mg PCB 169/kg bw, respectively. Upon birth all litters were mutually exchanged, thus creating 4 differently exposed groups of offspring: A) exposed neither in utero, nor during lactation; B) exposed in utero but not during lactation; C) exposed both in utero and during lactation; D) exposed during lactation, and not in utero. The F1-generation rats were mated with untreated partners of the same strain and age. Reproduction data of the treated males showed a reduced number of pregnancies in all treatment groups. Reproduction data of the treated females showed a decreased precoital time and number of pregnancies and an increased duration of gestation in the females of groups B and C. During the study morphological defects in the inguinal zone were detected both in treated males and females. Histological examination revealed a reduction in testis, epididymis and seminal vesicle weight and in number of epididymal spermatocytes in the males of group B, and an enlarged clitoris, reduced number of corpora lutea and multifocal endometrial epithelial hyperplasia in the females of groups B and C. Other parameters like vaginal opening, testes descent, anogenital distance, sperm physiology and morphology were not affected or showed minor differences between the groups. The results of the cross-fostering study show that the results found in the first study are caused by defects in the reproduction capacity of both in males and females. These reproduction defects are induced, particularly upon intrauterine exposure to PCB 169, while lactational exposure appeared less critical. (Waalkens-Berendsen et al, 1995)

Study #16

decrease in male pup weight
decrease in female weight at time of vaginal opening
decrease in testis weight at day 31, but increase at day 70
increase in urogenital distance in males
dosed from day 6 to day 22 of pregnancy
study used PCB commercial mix Aroclor 1254

Polychlorinated biphenyls (PCBs) have been shown to alter reproductive performance. Since PCBs are passed to offspring through the placenta and milk, effects of treatment of the dam on the development of the reproductive system in pups were studied. Female Sprague-Dawley rats were fed 4 mg/kg/day Aroclor 1254 from gestation day 6 until postpartum day 22. Pups were sacrificed on 15, 23, 31 and 70 days of age. Pup weight, male urogenital distance, time of vaginal opening, body weight at vaginal opening, reproductive organ weights and gross morphology of both sexes, and uterine moisture were determined. PCB treatment led to a 15% decrease in male pup weight at sacrifice, a 20% decrease in weight at vaginal opening, a decrease in testes weight at day 31 but an increase at day 70 of 10%, and a 15% increase in urogenital distance in males at 2 days of age. PCB treatment to dams seems to affect both the overall and reproductive growth and development of the offspring. (King et al, 1998)

Study #17

reduced uterine weight
reduced ovarian weight
reduced (or increased) testis weight
accelerated time of vaginal opening
reduced weight at time of vaginal opening
PCBs alters some toxicity of Methoxychlor
mixed overlapped dose timing
study used PCB commercial mix Aroclor 1254 and Methoxychlor (MXC)

Reproductive toxicity has been linked to the disruption of the endocrine system. Polychlorinated biphenyls (PCBs) bioaccumulate in the food chain and are passed on to offspring, inducing their cytochromes P450. Methoxychlor (MXC), a pesticide used as a substitute for DDT, has estrogenic properties. The objective of this study was to investigate whether basic reproductive parameters are altered by the gestational and lactational exposure to PCBs in combination with pre-weanling exposure to MXC. Female Sprague-Dawley rats were fed 4 mg/kg/day Aroclor 1254 from gestation day 6 until postpartum day 22. Pups (n = 745 total) were treated from postnatal days (PND) 10-14 with 0, 0.3, 3, or 300 mg/kg/day (IP) laboratory grade MXC in the vehicle safflower oil. Pups were sacrificed on PND 15, 23, 31, and 70. Day of vaginal opening, weight at vaginal opening, sacrifice weight (used as covariable where appropriate), and reproductive organ weights were determined. There was an interaction of PCBs by MXC on PND 15 (P less than 0.003) such that at 300 mg/kg/day MXC, control rats had greater ovarian weight (22 mg vs 11 mg) and greater uterine weight (38 mg vs 28 mg) than PCBs-treated rats. At PND 23, uterine weight was consistently suppressed by PCBs (P less than 0.0004). Testis weight was decreased at the highest dose of MXC at PND 15 and 31 (P less than 0.0001), but was increased by PCBs only on PND 23 (P less than 0.015). Day of vaginal opening (P less than 0.0001) was accelerated by 4 days and weight at vaginal opening (P less than 0.0006) was lowered by 25 g by the highest dose of MXC. PCBs appear to mitigate negative effects of the highest dose of MXC on ovarian and uterine weight, while positively affecting testis weight. (Respess et al, 1999)

Study #18

PCB 169 is an anti-androgen (anti- male hormone)
effects of PCB 169 bear little resemblance to those of any known anti-androgen.
study evaluated only PCB 169, plus 9 other suspected or known anti-androgens

Antiandrogenic chemicals alter sexual differentiation by a variety of mechanisms, and as a consequence, they induce different profiles of effects. For example, in utero treatment with the androgen receptor (AR) antagonist, flutamide, produces ventral prostate agenesis and testicular nondescent, while in contrast, finasteride, an inhibitor of 5 alpha-dihydrotestosterone (DHT) synthesis, rarely, if ever, induces such malformations. In this regard, it was recently proposed that dibutyl phthalate (DBP) alters reproductive development by a different mechanism of action than flutamide or vinclozolin (V), which are AR antagonists, because the male offsprings display an unusually high incidence of testicular and epididymal alterations--effects rarely seen after in utero flutamide or V treatment. In this study, we present original data describing the reproductive effects of 10 known or suspected anti-androgens, including a Leydig cell toxicant ethane dimethane sulphonate (EDS, 50 mg kg-1 day-1), linuron (L, 100 mg kg-1 day-1), p,p'-DDE (100 mg kg-1 day-1), ketoconazole (12-50 mg kg-1 day-1), procymidone (P, 100 mg kg-1 day-1), chlozolinate (100 mg kg-1 day-1), iprodione (100 mg kg-1 day-1), DBP (500 mg kg-1 day-1), diethylhexyl phthalate (DEHP, 750 mg kg-1 day-1), and polychlorinated biphenyl (PCB) congener no. 169 (single dose of 1.8 mg kg-1). Our analysis indicates that the chemicals discussed here can be clustered into three or four separate groups, based on the resulting profiles of reproductive effects. Vinclozolin, P, and DDE, known AR ligands, produce similar profiles of toxicity. However, p,p'-DDE is less potent in this regard. DBP and DEHP produce a profile distinct from the above AR ligands. Male offsprings display a higher incidence of epididymal and testicular lesions than generally seen with flutamide, P, or V even at high dosage levels. Linuron treatment induced a level of external effects consistent with its low affinity for AR [reduced anogenital distance (AGD), retained nipples, and a low incidence of hypospadias]. However, L treatment also induced an unanticipated degree of malformed epididymides and testis atrophy. In fact, the profile of effects induced by L was similar to that seen with DBP. These results suggest that L may display several mechanisms of endocrine toxicity, one of which involves AR binding. Chlozolinate and iprodione did not produce any signs of maternal or fetal endocrine toxicity at 100 mg kg-1 day-1. EDS produced severe maternal toxicity and a 45% reduction in size at birth, which resulted in the death of all neonates by 5 days of age. However, EDS only reduced AGD in male pups by 15%. Ketoconazole did not demasculinize or feminize males but rather displayed anti-hormonal activities, apparently by inhibiting ovarian hormone synthesis, which resulted in delayed delivery and whole litter loss. In summary, the above in vivo data suggest that the chemicals we studied alter male sexual differentiation via different mechanisms. The anti-androgens V, P, and p,p'-DDE produce flutamide-like profiles that are distinct from those seen with DBP, DEHP, and L. The effects of PCB 169 bear little resemblance to those of any known anti-androgen. Only in depth in vitro studies will reveal the degree to which one can rely upon in vivo studies, like those presented here, to predict the cellular and molecular mechanisms of developmental toxicity. (Gray et al, 1999)

Study #19

slight effects on cell proliferation and mammary gland development
study used PCB commercial mixtures Aroclor 1221 and 1254

We investigated mammary gland differentiation and cell proliferation in rats after acute exposure to xenoestrogens. Pubertal female Sprague-Dawley rats (six/group) were treated for 1 week with diethylstilbestrol (DES), genistein, o,p'-DDT, Aroclor 1221, Aroclor 1254, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or the vehicle, sesame oil. Animals were killed 18 hr after the last treatment. Analysis of mammary whole-mounts revealed that exposure to DES, genistein, and o,p'-DDT resulted in enhanced gland differentiation and increased epithelial cell proliferation as measured by proliferating cell nuclear antigen immunohistochemistry, TCDD treatment inhibited cell proliferation and gland development. Aroclor 1221 and Aroclor 1254 treatments had slight but not statistically significant effects on cell proliferation and mammary gland development. We conclude that DES, genistein, and o,p'-DDT given to pubertal rats act as morphogens; i.e., they increase cell proliferation, which promotes maturation of the u (incomplete abstract) (Brown et al, 1995)

Study #20

testicular weight increased
sperm numbers per cauda epididymus were decreased
daily sperm production reduced
persistent effects
study used PCB 18 and 60

It has been reported by different authors that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces reproductive hazards on male rats. PCB 77 is a non-ortho congener and is considered to possess "dioxinlike" activity. We have studied the reproductive effects of PCB 77 on adult male rats. The study was aimed to ascertain whether PCB 77 may cause TCDD like effects on the male reproductive system. Adult male rats (n = 15/group) were treated subcutaneously with a single dose of 18 mg/kg b.w. (PCB 18) or with 60 mg/kg b.w. (PCB 60). The substance was dissolved in a 10 mL volume of peanut oil/kg. The control rats received the same volume of the vehicle. The reproductive effects were investigated 1 and 4 weeks after treatment. The concentration of PCB was measured in liver, adipose tissue and testis. After 1 week, the absolute and relative testicular weights (g) were significantly increased in PCB 60 group (control: 1.63 +/- 0.1; PCB 60: 1.74 +/- 0.1). The sperm number (x10(6)) per cauda epididymis was significantly decreased in both PCB groups (control: 211 +/- 67;, PCB 18: 135 +/- 62; PCB 60: 142 +/- 49). Likewise the daily sperm production (x10(6)) was significantly reduced in PCB 18 as well as in PCB 60 group (control: 35 +/- 11; PCB 18: 21 +/- 8; PCB 60: 22 +/- 5). Moreover, the effects on spermatogenesis persisted 4 weeks after treatment (sperm number, control: 241 +/- 56; PCB 18: 166 +/- 53; PCB 60: 167 +/- 53), (daily sperm production, control: 36 +/- 5; PCB 18: 21 +/- 6; PCB 60: 17 +/- 5). The results demonstrate that PCB 77 affects sperm variables in a similar manner as TCDD when administered to adult rats. (Chahoud et al, 1997)

Go to Mouse and Rat Studies 21 to 47

Back to Human Health Risks

Back to Fox River Watch

To Site Index

Make a Donation