Dioxins Prostate Development and Cancer

Dioxins may cause prostate cancer, or make it more difficult to manage.

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Dioxins, Prostate Development and Cancer

Summary of Results

(each entry represents a finding in a study --- some studies had multiple findings)

dioxins caused decreased prostate weights [6 studies, plus those below]
dioxin exposure in the womb or through breastfeeding leads to severe inhibition in ventral prostate development accompanied by complete absence of branching morphogenesis
dioxin exposure in the womb or through breastfeeding interferes with prostate development by decreasing early epithelial growth, delaying cytodifferentiation, and altering epithelial and stromal cell histological arrangement.
may cause permanent changes in prostate spatial distribution of androgen receptor expression
AhR signaling (influenced by dioxins) may be involved, physiologically, in modulating prostate growth
dioxin exposure in the womb or through breastfeeding only decreased prostatic AhR on 7-day-old rats, which means it is unlikely that down-regulation of AhR is the mechanism by which perinatal TCDD exposure impairs prostate development.
dioxin exposure impairs prostate growth very early in development in the womb, resulting in decreased prostate weight well into adulthood
the hormonal environment in the womb may modulate the effects of dioxins on prostate (female-exposed males were affected, male-exposed males weren’t)
dioxin exposure in the womb or through breastfeeding selectively impairs prostate growth and development without inhibiting testicular androgen production or consistently decreasing prostate DHT concentration.
dioxin may cause incomplete imprinting of the male reproductive system during development in the womb
TCDD may alter the responsiveness of sex organs to steroids in adulthood
androgen responsiveness of the prostate is uniquely sensitive to dioxin exposure in the womb and through breastfeeding.
dioxin exposure inhibits imprinting of ventral prostate weight and protein but does not result in a universal inhibition of imprinting
dioxin exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation
dioxin acts both prenatally and postnatally to inhibit prostate growth and function, although prenatal exposure is far more effective than postnatal exposure
dioxin doses are most damaging to the prostate on certain days during gestation in the womb
dioxins caused delayed puberty
dioxins changed the sex ratio of births (male/female)
inhibition of prostatic bud formation is not due to inadequate DHT concentrations, instead dioxin may inhibit responsiveness of the UGS to DHT.
multiple mechanisms are possible, including interference with androgen receptor expression and/or signaling.
the most sensitive dioxin effects in male offspring included decreased ventral prostate
the developing prostate is sensitive to the effects of dioxin and DDE, which may augment one another's effects in this organ.
DHT-responsive genital organs [such as prostates] of male offspring are more sensitive to maternally transmitted dioxin
low doses of dioxin alters reproductive development and fertility of the progeny
alterations in these tissues [such as prostates] are not likely to have resulted from an alteration of the androgenic status of the male offspring
dioxin exposure during adulthood decreases ventral prostate weights and lowers plasma androgens
dioxin inhibits steroid hormone production in the testes
early dioxin exposure reduced the responsiveness of the prostate to androgen hormones later in life
the level of dioxin exposure via the placenta in the womb was lower than that via breastfeeding
dioxin caused decreases in plasma testosterone concentrations, and reductions in weights, protein, and DNA contents of ventral prostate
changes can be caused by low level exposure to dioxin in the womb alone
Dioxin decreased plasma androgen concentrations
Plasma testosterone concentrations in fetal males were significantly reduced
The surge in plasma testosterone concentrations shortly after birth was also significantly reduced,
decreased ventral prostate weights at the juvenile, pubertal, postpubertal, and mature stages of sexual development
dioxin can affect androgenic status without causing overt toxicity
the male reproductive system appears to be more sensitive to the toxic effects of in utero and lactational dioxin exposure than any other organ or organ system studied thus far.
dioxin produced transient reductions in ventral prostate weights
dioxins altered budding of the fetal prostate in the womb
dioxins induced cytochrome P450 1A1, but did not affect patterns of AhR and Arnt expression
changes were permanent and not caused by low testosterone in adulthood
dioxins reduced prostate weights by 32 to 44% through exposure in the womb

Studies of Dioxins and Prostate Development

The following are the results of 26 studies. Keep in mind that certain PCBs are “dioxin-like” in structure and function, and PCBs are often contaminated with dioxins. The types of PCBs which have lingered in our area and accumulated in Fox River and Green Bay fish are likely to be the more toxic and persistent PCB types (which are most similar to dioxin.)

Not all studies are equal in size or quality. Some studies were published in peer-reviewed journals, while others were simply presented at conferences. A few are duplicates by the same author (one conference-based, another published) but we presented both because the descriptions were slightly different. This is not a complete list of all studies on this topic. For more studies, visit the TOXNET database operated by the National Library of Medicine (the source of these abstracts).

Study #1

dioxins delayed prostate development [certain PCBs are dioxin-like, and are frequently contaminated with dioxins]

In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure decreases rat prostate weight without decreasing circulating androgen concentrations. Because one mechanism by which TCDD is thought to cause toxicity is by aryl hydrocarbon receptor (AhR)-mediated alterations in gene transcription, the goals of this study were to determine whether the developing prostate expresses the AhR and its dimerization partner, the AhR nuclear translocator (ARNT); to determine whether in utero and lactational TCDD exposure is capable of directly activating gene transcription in the developing prostate; and to identify prostatic mRNAs that exhibit altered abundance in response to in utero and lactational TCDD exposure. Pregnant Holtzman rats were administered TCDD (1.0 microgram/kg po) or vehicle on Gestation Day (GD) 15, and male offspring were euthanized between Postnatal Days (PNDs) 1 and 63. Using reverse transcriptase-polymerase chain reaction (RT-PCR), mRNAs encoding the AhR and ARNT were detected in both ventral and dorsolateral prostates from control animals throughout postnatal development. ARNT protein was expressed in the majority of stromal nuclei early in development, whereas ARNT expression in the prostate epithelium was initially cytoplasmic but became nuclear as development progressed. GD 15 TCDD exposure increased cytochrome P4501A1 (CYP1A1) mRNA and protein in whole prostates between PNDs 7 and 21. In these TCDD-exposed animals, CYP1A1 protein was localized to the epithelium. In order to define other genes in the developing prostate that might be regulated by TCDD at the level of mRNA, RNA samples from PND 21 whole prostates from control and TCDD-exposed animals were compared using mRNA differential display. Although no growth-regulatory candidates were identified using this screening technique, a ventral prostate-specific, androgen-regulated mRNA (20-kDa protein) was identified that seemed to be downregulated by TCDD exposure. Northern blot analysis confirmed this decrease at PND 21 and further showed that the downregulation was transient. Similar results were obtained for four additional androgen-regulated prostatic mRNAs (prostatic binding protein [PBP], Royal Winnipeg Ballet [RWB], probasin, and dorsal protein-1 [DP-1]), all of which are markers of a differentiated ductal epithelium. In contrast, TCDD exposure of adult male rats (25 micrograms TCDD/kg, 24 h) greatly induced CYP1A1 mRNA without affecting the abundance of prostate-specific, androgen-regulated mRNAs. These results suggest that the transient decreases in androgen-regulated prostatic mRNA abundance observed in response to in utero and lactational TCDD exposure were probably not the result of direct action of the activated AhR on these genes but instead were reflective of a TCDD-induced delay in prostate development. (Roman et al, 1998a)

Study #2

dioxin exposure in the womb or through breastfeeding leads to severe inhibition in ventral prostate development accompanied by complete absence of branching morphogenesis [certain PCBs are dioxin-like]

Branching morphogenesis is an essential component of prostate development. Previously we reported that in utero and lactational TCDD exposure inhibits ventral, dorsolateral, and anterior prostate growth. This study was conducted to test the hypothesis that TCDD inhibits branching morphogenesis in mouse prostate. Pregnant C57Bl/6 mice were given TCDD (5 ug/kg, po) or vehicle on Gestation Day 13 and their pups examined at 7, 14, 21, 35 and 90 days of age. Prostate lobes were microdissected after incubation in 0.5% collagenase and the numbers of main ducts, branch points, and ductal tips determined by examining photographs of microdissected, whole-mount specimens. Ductal canalization was determined using histological sections. TCDD inhibited branching morphogenesis in all prostate lobes. The ventral prostate was extremely small throughout development and never developed any ductal structure. TCDD reduced the numbers of main ducts, branch points, and ductal tips in the dorsal prostate, but reductions in branch point and ductal tip numbers appear to be due entirely to reductions in the number of main ducts. Duct length in the dorsal prostate also appeared to be shorter. The only noticeable effect of TCDD on lateral prostate structure was a reduction in duel length. Dorsolateral prostate weights were slightly reduced by TCDD, but there did not appear to be any effect on ductal canalization in either the dorsal or lateral lobes. TCDD had no effect on main duct number in the anterior prostate but weight, branch point number, and ductal tip number were substantially reduced. These results demonstrate that the severe inhibition in ventral prostate development caused by in utero and lactational TCDD exposure is accompanied by complete absence of branching morphogenesis, and that inhibitions in dorsal, lateral, and anterior prostate development are associated with lobe-specific inhibitions in branching morphogenesis. (Ko et al, 2001)

Study #3

dioxin exposure in the womb or through breastfeeding interferes with prostate development by decreasing early epithelial growth, delaying cytodifferentiation, and altering epithelial and stromal cell histological arrangement. [certain PCBs are dioxin-like]
may cause permanent changes in prostate spatial distribution of androgen receptor expression

In the male Holtzman rat, in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure decreases prostate weight without inhibiting testicular androgen production or decreasing circulating androgen concentrations. Therefore, the present study sought to characterize effects of TCDD exposure on prostate development, from very early outgrowth from the urogenital sinus (Gestation Day [GD] 20) until rapid growth and differentiation are essentially complete (Postnatal Day [PND] 32). Pregnant Holtzman rats were administered a single dose of TCDD (1.0 microgram/kg po) or vehicle on GD 15 and offspring were exposed via placental transfer (GD 20 euthanasia) or placental and subsequent lactational transfer until euthanasia (if before PND 21) or weaning. Results show that the prostatic epithelial budding process was impaired by in utero TCDD exposure, as evidence by significant decreases in the number of buds emerging from dorsal, lateral, and ventral aspects of the GD 20 urogenital sinus. Ventral prostate cell proliferation index was significantly decreased on PND 1 but was similar to or higher than control at later times, whereas apoptosis was an extremely rare event in ventral prostates from both control and TCDD-exposed animals. Delays were noted in the differentiation of pericordal smooth muscle cells and luminal epithelial cells. In addition, ventral prostates from approximately 40% of TCDD-exposed animals examined on PNDs 21 and 32 exhibited alterations in the histological arrangement of cell types that could not be explained by a developmental delay. Compared to controls, these ventral prostates exhibited a disorganized, hyperplastic epithelium containing fewer luminal epithelial cells and an increased density or continuous layer of basal epithelial cells, as well as thicker periductal smooth muscle sheaths. In addition, in ventral prostates from TCDD-exposed animals, the intensity of androgen receptor staining was relatively low in the central and distal epithelium, and the number of androgen receptor-positive cells was relatively high in the periductal stroma. These data suggest that in utero and lactational TCDD exposure interferes with prostate development by decreasing very early epithelial growth, delaying cytodifferentiation, and, in the most severely affected animals, producing alterations in epithelial and stromal cell histological arrangement and the spatial distribution of androgen receptor expression that may be of permanent consequence. (Roman et al, 1998b)

Study #4

AhR signaling (influenced by dioxins) may be involved, physiologically, in modulating prostate growth [certain PCBs are dioxin-like]

To determine if inhibitory effects of TCDD on prostate development are AhR-dependent and if AhR might play a physiological role in regulating prostate development, heterozygous (Ahr+/-) male and female mice (provided by Dr. Chris Bradfield) were mated and pregnant females treated with 5 ug TCDD/kg or vehicle on Gestation Day (GD) 13. Pups were weaned on postnatal day (PND) 21. Tissue was obtained from GD 18 fetuses and PND 10-16 pups for genotypic analysis by PCR. In utero and lactational TCDD exposure of wild-type (Ahr+/+) males inhibited ventral prostate (VP) growth to such an extent that on PND 21 the VP resembled that typically seen in control fetuses on GD 18. Ductal development was impaired and only 50% of the luminal epithelial cells expressed androgen receptor (AR) compared to almost 100% of luminal epithelial cells in control. By PND 35 VP, anterior prostate (AP), dorsal lateral prostate (DLP), and seminal vesicle (SV) weight were 12, 28, 47, and 50% of control, respectively. By PND 90, DLP and SV weights had recovered somewhat (to 68 and 71% of control values) but VP and AP weights were still only 15 and 27% of control. Significantly, TCDD failed to reduce prostate or SV weights in null mutant (Ahr-/-) males, demonstrating that the above effects of TCDD were AhR-dependent. The inhibitory effect of TCDD was also detected in the GD 18 fetus by a complete blockade of ventral prostatic bud formation, the initial step in ventral prostate development. Scanning EM examination of urogenital complexes on GD 18 revealed agenesis of ventral prostate buds in TCDD-exposed Ahr+/+ fetuses but no effect in their Ahr-/- littermates. To determine if AhR has a physiological role in male accessory sex organ growth, VP, DLP, AP, and SV weights were compared on PND 35 and PND 90 for males with different AhR genotypes from the same litter. There were 13-26% reductions in the weights of these organs in vehicle-exposed Ahr-/- males compared to Ahr+/+ males, suggesting that AhR signaling may be involved, physiologically, in modulating prostate growth. (Lin et al, 2000)

Study #5

dioxin exposure in the womb or through breastfeeding only decreased prostatic AhR on 7-day-old rats, which means it is unlikely that down-regulation of AhR is the mechanism by which perinatal TCDD exposure impairs prostate development. [certain PCBs are dioxin-like]

Effects of stage of development and 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) protein concentrations in reproductive organs of male rats were determined. AhR protein levels in developing rat ventral and dorsolateral prostate decreased with age, declining approximately 70% between Postnatal Days (PND) 1 and 21. ARNT protein levels also decreased with age in dorsolateral, but not ventral prostate. The developmental decreases in prostatic AhR and ARNT protein were associated with decreases in AhR and ARNT mRNA. AhR and ARNT protein concentrations in fetal urogenital sinus on Gestation Days (GD) 16, 18, and 20 were similar to levels in ventral prostate on PND 7. TCDD exposure of adult male rats (0.2, 1, 5, or 25 micrograms/kg po, 24 h) decreased AhR but not ARNT protein in ventral and dorsolateral prostate, vas deferens, and epididymis. In utero and lactational TCDD exposure (1.0 micrograms/kg dam po, GD 15) did not alter ARNT levels but reduced prostatic AhR protein levels on PND 7 and delayed the developmental decrease in AhR protein in ventral and dorsolateral prostate. Finally, pretreatment of rat pups for 24 h with TCDD (5 micrograms/kg ip) down-regulated prostatic AhR protein on PND 7, but not on PND 1. Thus, prostatic AhR and ARNT protein and mRNA levels are regulated with age, whereas only AhR protein concentration is altered by TCDD exposure. Because in utero and lactational TCDD exposure only decreased prostatic AhR on PND 7, it is unlikely that down-regulation of AhR is the mechanism by which perinatal TCDD exposure impairs prostate development. (Sommer et al, 1999)

Study #6

dioxin exposure impairs rat prostate growth very early in development in the womb, resulting in decreased prostate weight well into adulthood [certain PCBs are dioxin-like]
the hormonal environment in the womb may modulate the effects of dioxins on prostate (female-exposed males were affected, male-exposed males weren’t)

In utero 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure impairs rat prostate growth very early in development, resulting in decreased prostate weight well into adulthood. The highly branched ducts of the mature ventral, dorsal, and lateral lobes of the rat prostate begin as solid epithelial cords (prostatic buds) that bud from the fetal urogenital sinus between gestation days (GD) 18.5 and 20.5. To determine whether TCDD-induced decreases in prostate weight involve alterations in the epithelial budding process, pregnant Holtzman rats were administered TCDD (1.0 ug/kg, po) on GD 15, and male fetuses were caesarean delivered on GD 20. Because the fetal hormonal environment (and thus fetal prostate development) is influenced by intrauterine position, male fetuses were characterized as 2F (positioned between two females), 2M (positioned between two males), or 1M (positioned between one male and one female). Only 2F and 2M males were analyzed in this study. Shortly after delivery, fetuses were sacrificed and the entire urogenital complex was dissected. Serial sections of the urogenital complex were analyzed using computer-assisted reconstruction. In 2F males, in utero TCDD exposure decreased the number of prostatic epithelial buds to 65% of control in the ventral region, 70% of control in the dorsal region, and 67% of control in the lateral region. This inhibition of prostatic budding resulted in decreased total area of prostatic buds in all regions. In utero TCDD exposure did not significantly decrease the number of prostatic buds in 2M males, suggesting that the hormonal environment in utero may modulate the effects of in utero TCDD exposure on prostate development. (Roman et al, 1996)

Study #7

dioxin exposure in the womb or through breastfeeding selectively impairs prostate growth and development without inhibiting testicular androgen production or consistently decreasing prostate DHT concentration. [certain PCBs are dioxin-like]

To determine whether in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure decreases male rat accessory sex organ weights during postnatal development secondary to decreases in testicular androgen production or changes in peripheral androgen metabolism, pregnant Holtzman rats were administered a single dose of TCDD (1.0 microgram/kg, po) or vehicle on Gestation Day 15 and offspring were exposed via placental and subsequent lactational transfer until weaning on Postnatal Day (PND) 21. Between PNDs 21 and 63, circulating androgen concentrations and intratesticular androgen content tended to be decreased by in utero and lactational TCDD exposure, but in most cases decreases were not statistically significant. In vitro human chorionic gonadotropin-stimulated testosterone production by decapsulated testes from TCDD-exposed animals was not different from control, although 5 alpha-androstane-3 alpha,17 beta-diol production was decreased on PNDs 32 and 49 and increased on PND 63. Taken together, these results imply that in utero and lactational TCDD exposure can cause subtle decreases in testicular androgen production. However, the biological relevance of these reductions is equivocal because they do not correlate temporally with one another or with decreases in androgen-dependent male accessory sex organ weights. Of the male accessory sex organs, ventral prostate (VP) and dorsolateral prostate (DLP) were the most severely affected. Between PNDs 21 and 63, relative VP and DLP weights were decreased to 65-84% and 57-80% of control, respectively, and the magnitude of observed decreases was greatest at early times. In contrast, relative weights of the seminal vesicle and coagulating gland ranged from 80 to 104% of control, and the magnitude of observed decreases was greatest at later times. The sensitivity of the prostate to TCDD could not be explained by tissue-specific decreases in dihydrotestosterone (DHT) concentrations. Although VP DHT concentration was decreased to 63% of control on PND 21, DHT concentration was not decreased in the VP between PNDs 32 and 63 or in the DLP at any time. We conclude that in utero and lactational TCDD exposure selectively impairs rat prostate growth and development without inhibiting testicular androgen production or consistently decreasing prostate DHT concentration. (Roman et al, 1995)

Study #8

dioxin may cause incomplete imprinting of the male reproductive system during development in the womb [certain PCBs are dioxin-like]
TCDD may alter the responsiveness of sex organs to steroids in adulthood
androgen responsiveness of the prostate is uniquely sensitive to dioxin exposure in the womb and through breastfeeding.
dioxin exposure inhibits imprinting of ventral prostate weight and protein but does not result in a universal inhibition of imprinting

Previous studies strongly suggested that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may cause incomplete imprinting of the male reproductive system, i.e., that in utero and lactational exposure to TCDD may alter the responsiveness of sex organs to steroids in adulthood. To test this hypothesis, male rats born to dams dosed with 0.7 microgram TCDD/kg or vehicle on Gestation Day 15 were castrated at 63 days of age and implanted with graded lengths of Silastic capsule(s) containing crystalline testosterone. Resultant plasma testosterone concentrations ranged from castrate to about fourfold higher than physiological. Male reproductive organs which are imprinted by exposure to perinatal androgens and which are highly responsive to androgen stimulation in adulthood were assessed 3 weeks later. Ventral prostate weight and protein content in TCDD-exposed rats were significantly less responsive to testosterone regardless of the amount implanted. These decreases were not secondary to alterations in plasma or prostate testosterone or 5 alpha-dihydrotestosterone concentrations in adulthood, none of which was affected by TCDD. In contrast to its effects on ventral prostate weight and protein, TCDD had no effect on responsiveness to testosterone as measured by ventral prostate DNA content; seminal vesicle weight, protein content, or DNA content; penis weight; or plasma LH concentrations. We conclude that in utero and lactational TCDD exposure inhibits imprinting of ventral prostate weight and protein but does not result in a universal inhibition of imprinting. Androgen responsiveness of the prostate is uniquely sensitive to in utero and lactational TCDD exposure and provides a model to study the mechanism by which exposure to TCDD during fetal and early postnatal development modulates hormone-mediated responses in adulthood. (Bjerke et al, 1994)

Study #9

dioxin exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation [certain PCBs are dioxin-like]

In utero and lactational exposure to a single maternal dose of 1 microg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg causes some overt toxicity and impairs prostate growth in male offspring. As similar effects on the ventral prostate can be caused by decreased testosterone production during perinatal development, we determined whether intratesticular testosterone content, testicular responsiveness to gonadotropin stimulation, or plasma testosterone concentrations were reduced in fetal and newborn rats. Because these endpoints were not affected, the ability of TCDD exposure to inhibit synthesis of the proximal androgen in prostate development, 5alpha-dihydrotestosterone (DHT), from the circulating precursor testosterone and 5alpha-androstane-3alpha,17ss-diol (3alpha-Diol), was studied on postnatal days (PNDs) 14, 21, and 32. The ability of the ventral prostate to form DHT from 3alpha-Diol was slightly impaired on PND 14, but this transient effect was not statistically significant, and recovery was evident by PND 21. Subsequent experiments used organ culture to study the effects of in vivo TCDD exposure on androgen metabolism, androgen responsiveness, androgen receptor expression, and luminal epithelial cell differentiation after in vitro exposure to graded androgen concentrations. In utero and lactational TCDD exposure had no effect on DHT formation in organ culture, but transiently reduced the androgen -induced expression of prostatic-binding protein subunit C3, decreased ventral prostate epithelial cell androgen receptor expression, and inhibited the formation of androgen responsive luminal epithelial cells. These results suggest that TCDD exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation. (Theobald et al, 2000)

Study #10

dioxin acts both prenatally and postnatally to inhibit prostate growth and function, although prenatal exposure is far more effective than postnatal exposure [certain PCBs are dioxin-like]
dioxin doses are most damaging to the prostate on certain days during gestation in the womb

Among the most sensitive effects of in utero and lactational TCDD exposure is a permanent reduction of ventral prostate (VP) growth and development. The goals of this study were to determine the role of prenatal versus postnatal TCDD exposure in inhibiting VP growth and function, and to determine the most sensitive period of TCDD exposure. Pregnant C57Bl/6 mice were given 5 ug TCDD/kg or vehicle on Gestation Day (GD) 13 and litters were fostered at birth to dams of the same or opposite treatment. Four treatment groups were assessed: males not exposed to TCDD by either route (Control), and males exposed to TCDD in utero (IU), via lactation (L), or in utero and via lactation after GD 13 (IUL 13). A fifth group of male pups was exposed to the same dose of TCDD from GD 16 through weaning (IUL 16). Pups were weaned on Postnatal Day 21 and necropsied on Postnatal Day 35. Lactational TCDD exposure decreased VP weight to 59% of Control, while effects of IU exposure on VP weight were far more severe (8% of Control) and were similar to effects of IUL 13 exposure (14% of Control). However, a much less dramatic decrease was seen in IUL 16 males (29% of Control). Effects of TCDD on VP function were evaluated by mRNA abundance of an androgen-dependent, VP-specific secretory protein, MP25, using LightCycler real-time RT-PCR. The decrease in cyclophilin-normalized MP25 mRNA expression followed a pattern similar to that seen with VP weight. IU and IUL 13 TCDD exposure decreased expression to 3%, IUL 16 to 11%, and L to 42% of Control. These results demonstrate that TCDD acts both prenatally and postnatally to inhibit VP growth and function, although prenatal TCDD exposure is far more effective than postnatal exposure. Furthermore, exposure to TCDD between GD 13 and GD 16 appears to be the most sensitive period for impairing VP development. (Simanainen et al, 2001)

Study #11

dioxins caused decreased prostate weights [certain PCBs are dioxin-like]
dioxins caused delayed puberty
dioxins changed the sex ratio of births (male/female)

In utero and lactational exposure to TCDD results in a wide variety of developmental effects in pups at doses much lower than those causing overt toxicity in adult animals. An appropriate dosimetry to predict adverse developmental effects is needed in risk assessment of TCDD. The objective of this study was to investigate the relationship between tissue concentrations of TCDD in dams and fetuses and developmental effects on pups in the same set of experiments. Pregnant Long-Evans rats were given a single oral dose of 12.5, 50, 200 or 800 ng of cold or (3H)-TCDD/kg bw on gestation day (GD)15. Dams were sacrificed on GD16 and GD21, and tissue concentrations of TCDD were measured in dams and fetuses. Pups were sacrificed on postnatal day (PND)49 and PND63 for male and PND70 for female, and reproductive effects and tissue concentrations of TCDD were determined. Sex ratio (male/female) was significantly reduced at 50 ng TCDD/kg on GD21, and at 12.5 and 50 ng TCDD/kg at birth, but not at other doses. It is not known whether this reduced sex ratio is incidental or low-dose effect. Delayed puberty was observed in males at 200 ng TCDD/kg and in males and females at 800 ng TCDD/kg with lower body weight gain. Anogenital distance, testis weight, epididymal sperm count, sperm motility and ejaculated sperm count were not affected by maternal TCDD exposure. Estrous cyclicity was not different from control at any treatment groups. A dose-dependent decrease in seminal vesicle and prostate weights on PND 49 was observed. Prostate weight was significantly decreased at 800 ng TCDD/kg. At this dose, maternal adipose tissue concentration and fetal concentration were 512 pg TCDD/g and 52 pg TCDD/g on GD16, respectively. These body burdens correspond to the reduced prostate weight. (Yonemoto et al, 2001)

Study #12

dioxin exposure in the womb and through breastfeeding permanently impairs prostate growth [certain PCBs are dioxin-like]
inhibition of prostatic bud formation is not due to inadequate DHT concentrations, instead dioxin may inhibit responsiveness of the UGS to DHT.
multiple mechanisms are possible, including interference with androgen receptor expression and/or signaling.

In utero and lactational TCDD exposure permanently impairs prostate growth. This effect can be detected by Gestation Day (GD) 18, when the formation of prostatic buds from the urogenital sinus (UGS), the initial step in prostate development, is impaired. Scanning electron microscopy (SEM) of UGS complexes on GD 18 revealed agenesis of ventral buds and decreased numbers of dorsolateral buds in TCDD-exposed Ahr+/+ (wild-type) fetuses but no effect in their Ahr-/- (AhRKO) littermates. Budding from the UGS is DHT-dependent. We hypothesized that the impairment in prostatic budding caused by in utero TCDD exposure is not due to possible reductions in DHT formation. To test this hypothesis, sustained-release DHT-containing or control pellets were implanted sc in pregnant mice on GD 12, dams were given TCDD (5 ug/kg) or vehicle on GD 13, and budding was examined on GD 18. Maternal DHT concentrations were high (5 ng/mL serum), and fetuses were severely masculinized, as evidenced by enlarged external genitalia and increased anogenital distance among female fetuses. UGS complexes were subjected to limited trypsin digestion to separate epithelium from mesenchyme. UGS epithelium was examined by SEM. Prenatal DHT exposure increased the number of dorsolateral buds in vehicle-exposed wild-type and AhRKO pups by 5% and 25%, respectively. However, DHT did not protect against the inhibition of prostatic bud formation caused by TCDD. Ventral bud formation was still completely blocked, and dorsolateral bud number was reduced from 74% of control in TCDD-exposed wild-type fetuses to 52% of control in DHT- and TCDD-exposed wild-type fetuses. These results demonstrate that the inhibition of prostatic bud formation is not due to inadequate DHT concentrations, and suggest that TCDD inhibits responsiveness of the UGS to DHT. Multiple mechanisms are possible, including interference with androgen receptor expression and/or signaling. (Lin et al, 2001)

Study #13

the most sensitive dioxin effects in male offspring included decreased ventral prostate [certain PCBs are dioxin-like]

To evaluate effects of in utero and lactational 2,3,7,8-tetrachlorodibenzo-rho-dioxin (TCDD) exposure on male and female reproductive system development of the mouse, the offspring of pregnant ICR mice administered 0, 15, 30, or 60 microg TCDD/kg on Gestation Day (GD) 14 were examined at the postweanling, pubertal, young adult, and adult stages of development. Dam and offspring body weights and prenatal and postnatal mortality were unaffected by TCDD exposure. The most sensitive endpoints in male offspring were decreased ventral prostate, coagulating gland, and thymus weights, accelerated eye opening, and hydronephrosis. Decreases in pituitary gland weight and epididymal sperm numbers were also found in TCDD-exposed male offspring. Testis, epididymis, and dorsolateral prostate weights, anogenital distance, latencies to testis descent and to preputial separation, and serum testosterone concentrations were unaffected. At the highest maternal TCDD dose uterus weights were decreased in female offspring evaluated during estrus and diestrus. No morphologic changes in the external genitalia of female offspring were found, nor were there alterations in ovary or pituitary gland weights. Cross-species comparisons showed that the mouse was not as sensitive to TCDD-induced developmental reproductive toxicity as the rat and hamster. Many endpoints affected by TCDD in rat and hamster offspring were either not affected or were less sensitive in mouse offspring. Endpoints of androgenic status were not affected in the mouse, decreases in accessory sex organ weights were restricted to fewer organs in the mouse, and decreases in daily sperm production were not found in the mouse. The only developmental reproductive endpoint observed in all three species was a reduction in epididymal sperm numbers. (Theobald et al, 1997)

Study #14

the developing prostate is sensitive to the effects of dioxin and DDE, which may augment one another's effects in this organ. [certain PCBs are dioxin-like]

The developing male rat reproductive system is highly sensitive to low doses of TCDD and p,p'-DDE (DDE), which exert antiandrogenic effects via different mechanisms. This study investigates the interactive effects of in utero and lactational exposure to a mixture of these compounds. Pregnant Holtzman rats received one of the following: vehicle on gestation day (GD) 14-18, 0.25 microgram/kg TCDD on GD15, 100 mg/kg DDE on GD 14-18, or 0.25 microgram/kg TCDD on GD15 and 100 mg/kg DDE on GD 14-18. Male offspring were euthanized on postnatal day (PND) 21 (weaning), PND 32 (prepuberty), PND 49 (puberty), and PND 63 (postpuberty). Coadministration of these doses of TCDD and DDE appeared to potentiate their individual actions on prostate weight on PND 21, while immunostaining for the prostatic androgen receptor exhibited patterns characteristic of the effects of both compounds individually. Cauda epididymal sperm number was reduced by each compound but was not further reduced by exposure to TCDD and DDE in combination. Anogenital distance, age at onset of puberty, daily sperm production, testicular and accessory sex organ weight (nonprostate), and levels of prostatic androgen-regulated gene transcripts are affected at higher doses of both compounds, but not at the doses used in the present study. Only DDE-treated animals retained nipples on PND 13. Serum androgen levels did not differ between treatment groups. In conclusion, the developing rat prostate is uniquely sensitive to the effects of TCDD and DDE, which may augment one another's effects in this organ. (Loeffler et al, 1999)

Study #15

DHT-responsive genital organs [such as prostates] of male offspring are more sensitive to maternally transmitted dioxin [certain PCBs are dioxin-like]

The effects of dioxins on the reproductive and developmental functions of fetuses are of great concern, since fetuses are very sensitive to chemicals and effects suffered in fetal life are often irreversible. The purpose of the present study is to obtain basal data for the risk assessment of the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the reproductive, endocrine, and immunological functions of male offspring. Pregnant Holtzman rats (CR) were given a single oral dose of 0, 12.5, 50, 200, or 800 ngTCDD/kg body weight on gestational day 15, and the male offspring were sacrificed on Days 49, 63, and 120 after birth. Serum T4 level was significantly decreased at 800 ng/kg on Day 63. Cellular hyperplasia of the follicle and hypertrophy of the thyroid glands (2/12) were observed at 800 ng/kg on Day 120. Serum T3 and TSH levels were not affected at any stages. Spleen cell numbers were significantly decreased dose-dependently on Day 49. Thymus cell numbers were decreased dose-dependently on day 120. No significant effects of TCDD were observed in testes' weight, daily sperm production, epididymal weight, and sperm reserve in the cauda epididymis of the offspring. However, among sex-accessory glands, ventral prostate weight was significantly reduced at 800 ng/kg on Day 49 and at 200 and 800 ng/kg on Day 120. Additionally, the anogenital distance was significantly decreased at 50 and 800 ng/kg on Day 63 and over 50 ng/kg on Day 120. It is known that testes and epididymis are responsive to testosterone, while external genitalia and ventral prostate are responsive to 5alpha-dihydrotestosterone (DHT), which is converted from testosterone. It is suggested that the DHT-responsive genital organs of male offspring are more sensitive to maternally transmitted TCDD. (Yonemoto et al, 1999)

Study #16

low doses of dioxin alters reproductive development and fertility of the progeny [certain PCBs are dioxin-like]
alterations in these tissues [such as prostates] are not likely to have resulted from an alteration of the androgenic status of the male offspring

Prenatal administration of relatively low doses of TCDD alters reproductive development and fertility of the progeny. Fertility was reduced in the progeny of Wistar rats exposed to 0.5 micrograms TCDD/kg/day from Gestational Day (GD) 6 to GD 15. In a three-generation reproduction study, TCDD reduced fertility of Sprague-Dawley rats in the F1 and F2 but not the F0 (no developmental exposure) generation at 0.01 microgram/kg/day in the diet. Furthermore, administration of TCDD on GD 15 (at 0.064 to 1 microgram/kg) both demasculinized and feminized morphology and behavior of Holtzman male rat offspring. Our objectives were to expand the observations of Mably et al. (1992, Toxicol, Appl. Pharmacol. 114, 97-107, 108-117, 118-126) on the effects of gestational administration of a single dose of TCDD to another strain of rat and another species, the hamster. In the first study, Long Evans (LE) hooded rats were dosed by gavage with 1 microgram TCDD/kg on GD 8 (during the period of major organogenesis) or GD 15 (the gestational day used by Mably et al.). In the second study, pregnant Syrian hamsters, a species relatively insensitive to the lethal effects of TCDD, were dosed on GD 11, equivalent to GD 15 in the rat, with TCDD at 2 micrograms/kg. When LE rats were dosed on GD 15, or when hamsters were dosed on GD 11, puberty (preputial separation) was delayed by about 3 days, ejaculated sperm counts were reduced by at least 58%, and epididymal sperm storage was reduced by 38%. Testicular sperm production was less affected. The sex accessory glands were also reduced in size in LE rat offspring treated on GD 15 despite the fact that serum testosterone (T), T production by the testis in vitro, and androgen receptor (AR) levels were not reduced. Some reproductive measures, such as anogenital distance and male sex behavior, were altered by TCDD treatment in rat but not hamster offspring. Since T and AR levels appeared normal in the sex accessory glands and the epididymis following perinatal TCDD exposure, the alterations in these tissues are not likely to have resulted from an alteration of the androgenic status of the male offspring. (Gray et al, 1995)

Study #17

dioxin exposure during adulthood decreases ventral prostate weights and lowers plasma androgens [certain PCBs are dioxin-like]
dioxin inhibits steroid hormone production in the testes

TCDD exposure during adulthood decreases seminal vesicle (SV) and ventral prostate (VP) weights and lowers plasma androgens in male rats, in part, by inhibiting testicular steroidogenesis. Since perinatal TCDD exposure also decreases SV and VP weights, our objective was to determine whether this treatment regimen similarly impairs testicular androgen production. Dams were dosed with TCDD (1 ug/kg, po) or vehicle on gestation day 15, and lactational exposure continued until weaning (postnatal day 21). On days 21, 32, 49, and 63, SV and VP weights and plasma and intratesticular testosterone (T) and 5-alpha-androstan-3-alpha,17-beta-diol (alpha-diol) were measured. In vitro responsiveness to the LH analog human chorionic gonadotropin (hCG) was assessed by measuring T and alpha-diol produced by decapsulated testes incubated with 9 graded concentrations of hCG (0 to 51.2 mIU/mL). TCDD significantly decreased VP weights at all times (to 59-83% of control) and significantly decreased SV weights on days 32 and 63 (to 85% of control). In TCDD-exposed animals, plasma and intratesticular androgen concentrations ranged from 62 to 100% and 49 to 107% of control, respectively. At most times, these decreases were not statistically significant. In addition, hCG-stimulated androgen production by testes from TCDD-exposed animals was not different from control. We conclude that, in contrast to adult exposure, the mechanism by which perinatal TCDD exposure decreases VP and SV weights does not involve inhibition of testicular androgen production. (Roman et al, 1994)

Study #18

early dioxin exposure reduced the responsiveness of the prostate to androgen hormones later in life [certain PCBs are dioxin-like]

The purpose of this study was to investigate the mechanism by which perinatal TCDD exposure decreases accessory sex organ weights in adult male rats. These weights are heavily dependent on the degree of androgen stimulation, and while perinatal TCDD exposure tends to reduce plasma androgen concentrations in adulthood, these reductions are generally not statistically significant. We therefore tested the hypothesis that perinatal TCDD exposure decreases the responsiveness of the accessory sex organs to androgen stimulation. Pregnant Holtzman rats were orally dosed with 0.7 ug TCDD/kg or vehicle on Day 15 of pregnancy. Postnatal exposure was terminated by weaning (Day 21). In adulthood, rats were castrated and implanted with Silastic capsules containing graded amounts of crystalline testosterone. This produced a wide range of plasma testosterone concentrations (from castrate to supraphysiological). After three weeks, rats were euthanized and the seminal vesicles (SV) and ventral prostate (VP) were removed, weighed, and frozen for subsequent determinations. Results indicate that decreased androgen responsiveness contributes to a decrease in VP weight, while perinatal TCDD exposure had no effect on SV androgen responsiveness. Rats that were perinatally exposed to TCDD required implants approximately twice as long as those in control rats to achieve the same VP weight. (Bjerke et al, 1993)

Study #19

dioxin significantly reduced the weight of the ventral prostate [certain PCBs are dioxin-like]
the level of dioxin exposure via the placenta in the womb was lower than that via breastfeeding

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on placenta, the male reproductive function, thyroid function and immune function of offspring were investigated. Transference of TCDD from dams to offspring was also investigated. Pregnant Holtzman rats were given a single oral dose of TCDD (12.5, 50, 200 or 800 ng/kg bw) on gestational day (GD) 15, and male offspring were sacrificed on postnatal day (PND) 21, 49 or 120. The maturation of the placenta, the proliferation of spongiotrophoblast cells and reduction of the area occupied by glycogen cells in the junctional zone, was affected by TCDD. Prolactin family genes, which were expressed in spongiotrophoblast cells, were down-regulated in the TCDD-treated placenta on GD20. Among sex-accessory glands, the weight of the ventral prostate was significantly reduced at 800 ng TCDD/kg on PND49 and at 200 and 800 ng TCDD/kg on PND120. Additionally, the anogenital distance, the length of the body of the penis, was decreased at doses of TCDD exceeding 50 ng/kg on PND120. However, the development of the testis and epididymis, including spermatogenesis and sperm reserve, was not affected by TCDD. These results suggest that the development of 5alpha-dihydrotestosterone (DHT)-responsive tissues and organs is sensitive to maternal TCDD exposure. The serum thyroxine (T4) level was significantly decreased at TCDD doses of 200 and 800 ng/kg at PND21. However, the T4 level recovered to the control level by PND49. UGT-1, which glucuronidizes T4, was significantly induced by 200 and 800 ng TCDD/kg at PND21, but no such induction was observed at PND49. It is suggested that TCDD-dependent induction of UGT-1 and subsequently enhanced biliary excretion of T4 via glucuronidation are involved in the reduction of circulating T4 at PND21. The amount of TCDD transferred from dam to fetuses was increased from 0.7 ng/liter on GD16 to 2.0 ng/litter on GD20. At weaning, each individual pup contained 14.2 ng of TCDD suggesting that the level of TCDD exposure via the placenta was lower than that via lactation. (Yonemoto, 2001)

Study #20

dioxin caused decreases in plasma testosterone concentrations, and reductions in weights, protein, and DNA contents of ventral prostate [certain PCBs are dioxin-like]
changes can be caused by low level exposure to dioxin in the womb alone

The male rat reproductive system is highly sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) when exposure occurs during fetal and neonatal development. Our objective was to determine the relative contributions of in utero versus lactational TCDD exposure to effects on male reproductive function. Pregnant Holtzman rats were treated on Day 15 of gestation with TCDD (1.0 micrograms/kg) or vehicle (control). At birth litters were standardized to five males and five females and fostered to dams of the same treatment or cross-fostered to dams of the opposite treatment. Four treatment groups were assessed: male offspring not exposed to TCDD by either route (control) and male offspring exposed to TCDD in utero (IU), via lactation (L), or in utero and via lactation (IUL). During early postnatal development, two androgen sensitive end points, relative anogenital distance and time to testis descent, were not affected by TCDD. However, end points evaluated later during development were altered. Time to separation of the prepuce from the glans penis (an index of pubertal development) was delayed, plasma testosterone concentrations and accessory sex organ weights were reduced, daily sperm production and epididymal sperm reserves were decreased, and sexual behavior was feminized. Certain responses were only produced by IU exposure whereas other responses only occurred following L exposure. Only IU TCDD exposure delayed pubertal development and decreased daily sperm production, while only L TCDD exposure feminized the sexual behavior of male offspring. For most male reproductive end points both IU and L TCDD exposure produced the same responses. Decreases in plasma testosterone concentrations, reductions in weights, protein, and DNA contents of ventral prostate and seminal vesicles, and decreases in epididymal sperm reserves were caused in young adult rats by either IU or L exposure to TCDD. We conclude that the route and timing of TCDD exposure during fetal and neonatal development of the rat determine the profile of male reproductive effects observed and that all effects in the present study, with the notable exception of feminized sexual behavior, can be caused by low level exposure to TCDD via the IU route alone. (Bjerke et al, 1994)

Study #21

Dioxin decreased plasma androgen concentrations [certain PCBs are dioxin-like]
Plasma testosterone concentrations in fetal males were significantly reduced
The surge in plasma testosterone concentrations shortly after birth was also significantly reduced
decreased ventral prostate weights at the juvenile, pubertal, postpubertal, and mature stages of sexual development
dioxin can affect androgenic status without causing overt toxicity
the male reproductive system appears to be more sensitive to the toxic effects of in utero and lactational dioxin exposure than any other organ or organ system studied thus far

When administered in overtly toxic doses to postpubescent rats, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces a variety of adverse effects on the male reproductive system including a decrease in plasma androgen concentrations. If such an androgenic deficiency were produced prenatally and/or early postnatally it could potentially impair male reproductive function by disrupting the development of sex organs and/or causing incomplete sexual differentiation of the central nervous system. To determine whether TCDD can reduce androgen concentrations perinatally and/or impair androgen-dependent perinatal development, pregnant Holtzman rats were treated with 1.0 micrograms TCDD/kg or vehicle on Day 15 of gestation. Plasma testosterone concentrations in fetal males were significantly reduced by TCDD on Gestation Days 18 through 21. The surge in plasma testosterone concentrations shortly after birth was also significantly reduced, as was anogenital distance, an androgen-dependent parameter. To further investigate the effects of perinatal TCDD exposure on the male reproductive system, rats born to dams given TCDD (0.064, 0.16, 0.40, or 1.0 micrograms/kg, po) or vehicle on Day 15 of gestation were evaluated from birth through sexual maturation. This report describes their growth, physical development, and androgenic status (i.e., androgen concentrations and androgen-dependent structures and functions); effects on spermatogenesis, testicular histology, sexual behavior, and fertility are reported separately. There was little evidence that TCDD caused maternal toxicity. Signs of overt toxicity in offspring were limited to an 8% reduction in live births (highest dose only) and to decreases in body weight gain and feed consumption (two highest doses only) which disappeared by early adulthood. With respect to androgenic status, maternal TCDD doses as low as 0.16 micrograms/kg produced significant dose-related decreases in the anogenital distance of 1- and 4-day-old males, delays in testicular descent, and decreases in seminal vesicle and ventral prostate weights. The reductions in organ weights were observed when rats were at the juvenile, pubertal, postpubertal, and mature stages of sexual development. Plasma testosterone and 5 alpha-dihydrotestosterone concentrations tended to be reduced at these times (though not significantly), while plasma luteinizing hormone concentrations were generally unaffected. Collectively, these results demonstrate that perinatal TCDD exposure alters the androgenic status of male rats from the fetal stage into adulthood, and that TCDD can affect androgenic status without causing overt toxicity. In rats, the male reproductive system appears to be more sensitive to the toxic effects of in utero and lactational TCDD exposure than any other organ or organ system studied thus far. (Mably et al, 1992)

Study #22

prostate was slightly reduced in size by dioxin [certain PCBs are dioxin-like]

Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on endocrine functions during developmental stage has gained much attention in terms of health risk assessment of this highly toxic compound. Some researchers reported that the transplacental exposure to TCDD during developmental stage of fetuses caused reproductive disorders, including decrease of sperm numbers, reduced size of genital organs, and also feminized behavior. We here examined relatively low dose TCDD effects on male reproductive system. Pregnant Holtzman rats (JCR) were given a single oral dose of 0, 12.5, 50, 200 or 800 ng TCDD/kg body weight on gestation Day 15, and male offspring were sacrificed on Day 2, 49 or 63 after birth. There was no TCDD effects in litter size, birth weight and sex ratios of pups for all groups. Anogenital distance of Day 2, 49 and 63 male rats showed a significant decrease in the highest dose of TCDD. Prostate was slightly reduced in size. However, there were no changes on testis and epididymal weights by TCDD administration even at the 800 ng/kg dose on Day 49 and 63. In addition, daily sperm production and sperm reserve on Day 63 were not changed by TCDD. GC/MS analysis with the abdominal fat tissue clearly showed the increased amounts of TCDD were still retained in these offspring. These results suggested that relatively low dose of TCDD could affect the external genital organs, but the internal genital organs including testis seems to be less sensitive. (Ohsako et al, 1999)

Study #23

dioxin produced transient reductions in ventral prostate weights [certain PCBs are dioxin-like]

Male rats exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) display reduced fertility as a consequence of the direct action of TCDD on the epididymides, as well as delayed puberty and altered reproductive organ weights. The current study provides dose-response data for the reproductive effects of TCDD, administered during pregnancy, with an emphasis on the effects of TCDD on testicular, epididymal, and ejaculated sperm numbers. Long Evans Hooded rats were dosed by gavage with 0, 0.05, 0.20, or 0.80 microg TCDD/kg on Day 15 of gestation. After birth, growth, viability, and developmental landmarks were monitored in both male and female offspring. Shortly after puberty (49 and 63 days of age) and at 15 months of age, male offspring were necropsied. Growth and viability of the pups were reduced only at 0.80 microg TCDD/kg, eye opening was accelerated (all dosage groups), and puberty was delayed (at 0.20 and 0.80 microg TCDD/kg). Treated progeny displayed transient reductions in ventral prostate and seminal vesicle weights, while epididymal sperm reserves and glans penis size were permanently reduced. Ejaculated sperm numbers were reduced (45% in the 0.8 and by 25% in the 0.05 and 0.2 microg TCDD/kg dosage groups) to a greater degree than were cauda or caput/corpus epididymal or testicular (unaffected) sperm numbers. In conclusion, administration of TCDD on Day 15 of pregnancy at 0.05 microg/kg altered eye opening and reduced ejaculated sperm counts, while higher dosage levels also delayed puberty and permanently reduced cauda epididymal sperm reserves. (Gray et al, 1997)

Study #24

dioxins altered budding of the fetal prostate in the womb [certain PCBs are dioxin-like]
dioxins induced cytochrome P450 1A1, but did not affect patterns of AhR nad Arnt expression

A gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to alter male reproductive development in rats (Mably et al., 1992; Gray et al., 1995). In utero and lactational exposure to TCDD resulted in alterations in the budding of the fetal prostate as well as postnatal epithelial differentiation and smooth muscle thickness (Roman et al., 1998). In postnatal day (PND) 32 rat pups, TCDD-induced decreases in seminal vesicle weight appear to result from altered epithelial development (Hamm et al., 2000). This study examines the effects of TCDD on the expression of Ah receptor, Arnt and CYP1A1 in exposed rat pups using real-time PCR. Time-pregnant Long-Evans rats were treated orally with 1.0 ug TCDD/kg of body weight on gestational day 15. Male pups were sacrificed on PNDs 4, 10, 25, and 32 and whole body and paired seminal vesicle weights were recorded. Tissues were collected and stored at -80 degrees C until analyzed. Seminal vesicle weights were not significantly different between control and exposed animals at PNDs 4, 10, and 25, but by PND 32 exposed animals had lower seminal vesicle weights (59.6 +/- 11.1 versus 36.7 +/- 9.4 mg) in comparison to control animals. A time-dependent increase in TCDD-induced CYP1A1 mRNA expression reached a maximum at PND 10 in seminal vesicle as compared to controls followed by a time-dependent decrease. While there were no significant differences in AhR and Arnt mRNA expression between control and treated animals, a slight decrease at PND 32 was observed in Ahr and Arnt mRNA expression for both control and TCDD exposed seminal vesicles. This study demonstrates that in utero and lactational exposures to TCDD results in an induction in cytochrome P450 1A1 and a significant decrease in seminal vesicle weights while not affecting the pattern of AhR and Arnt expression. (Richardson et al, 2001)

Study #25

dioxins reduced prostate weights through exposure in the womb [certain PCBs are dioxin-like]
changes were permanent and not caused by low testosterone in adulthood

In utero and lactational exposure to TCDD inhibits spermatogenesis, decreases sex organ weights, and demasculinizes sexual behavior in young adult male rats. To determine if these effects can be reversed with time and/or testosterone treatment, males born to dams given 1.0 ug TCDD/kg or vehicle on Day 15 of gestation were evaluated at 10-12 months of age. Testis, epididymis, and cauda epididymis weights, daily sperm production, and cauda epididymal sperm counts in TCDD-exposed rats were significantly reduced. Sexual behavior was greatly demasculinized both before and after castration and physiological testosterone replacement. Seminal vesicle, ventral prostate, and glans penis weights were significantly smaller in TCDD-exposed, castrated, testosterone-implanted rats than in control rats, while the numbers of penile papillae were either not affected by TCDD or slightly increased. This study indicates that in utero and lactational TCDD exposure can permanently inhibit spermatogenesis and demasculinize sexual behavior. Demasculinization is not caused by low plasma testosterone concentrations in adulthood, nor can it be attributed to a reduction in the number of penile papillae. Finally, in utero and lactational TCDD exposure appears to decrease the responsiveness of male sex organs to androgens. (Moore et al, 1992)

Study #26

dioxins reduced prostate weights by 32 to 44% through exposure in the womb [certain PCBs are dioxin-like]

Treatment of pregnant female Sprague-Dawley rats on Gestational Day 15 with a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.5, 1.0, or 2.0 micrograms/kg) or indole-3-carbinol (I3C, 1.0 or 100 mg/kg), an aryl hydrocarbon (Ah) receptor agonist which is found in cruciferous vegetables, resulted in reproductive abnormalities in the male offspring (three to five litters in each treatment group). Anogenital distance and crown to rump length were altered by both compounds; however, the timing of the effects (Day 1 or 5) was variable and the responses were not necessarily dose-dependent. In 62-day-old offspring, seminal vesicle (24 to 26%), prostate (32 to 44%), testicular parenchymal (14%), and epididymal weight (19%) were decreased by one or more doses of TCDD. In contrast, I3C at one or more doses decreased daily sperm production/g testicular parenchyma (13 to 20%) and daily sperm production/testis (22%). Total number of sperum in the epididymis was significantly decreased (30 to 33%) in rats perinatally exposed to TCDD and this was due to a decreased (49 to 51%) number of sperm in the tail of the epididymis. Perinatal exposure to I3C did not affect any of these parameters. TCDD did not affect epididymal transit time of sperm through the complete epididymis at any of the doses (0.5 to 2.0 micrograms/kg). However, at the two highest doses (1.0 and 2.0 micrograms/kg), TCDD increased epididymal transit rate of sperm through the tail of the epididymis by 33 and 37%, respectively. In contrast, primarily due to decreased transit rate (39%) of sperm through the head plus body of the epididymis. I3C (1 mg/kg) significantly increased total epididymal transit time by 31%. In conclusion, perinatal exposure of pregnant rats to I3C, an Ah receptor agonist similar to TCDD, causes reproductive abnormalities in male rat offspring; however, I3C and TCDD elicited both common and different responses. (Wilker et al, 1996)

Study #27

dioxins reduced ventral prostate weights, due to deficiency in male hormone androgen [certain PCBs are dioxin-like]

Following sexual maturation, the reproductive system of male rats is relatively resistant to TCDD. This study was designed to determine the sensitivity of male rats to perinatal TCDD exposure. Female rats were given TCDD (0.0, 0.064, 0.16, 0.40, or 1.0 ug/kg, po) on day 15 of pregnancy, thus exposing their offspring in utero and via lactation. The percentage of live births was slightly decreased (highest dose only), while no effects on maternal weight gain, litter size, or offspring survival were seen. A decrease in body weight seen in day-old pups was maintained into adulthood (typically 10-15% at the highest dose). Of the developmental indices measured (time to pinna detachment, incisor eruption, eye opening, and testis descent), only testis descent was delayed. Dose-related decreases in the weights of androgen-dependent organs (seminal vesicles and ventral prostate) were seen on days 32, 49, 63, and 120; plasma testosterone and dihydrotestosterone concentrations were similarly affected. Dose-related decreases in anogenital distances of 1- and 4-day old males also suggest the presence of an androgenic deficiency. Thus, male rats are sensitive to perinatal TCDD exposure; maternal doses as low as 0.16 ug/kg appeared to cause a perinatal androgenic deficiency that persisted into adulthood. (Moore et al, 1990)

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