Androgens and environmental antiandrogens affect reproductive development and play behavior in the Sprague-Dawley rat.
Open accessAbstract
In mammals, exposure to androgens early in development is essential for masculinization of the male reproductive phenotype. Male fetuses exposed to antiandrogens during perinatal life are permanently demasculinized in their morphology and physiology, whereas exposure to exogenous androgens permanently masculinizes females. In some litter-bearing species, proximity(italic) in utero(/italic) of females to males can partially masculinize female siblings and alter their responsiveness to endocrine-disrupting compounds. However, in our strain of rat (CD-SD Charles River), intrauterine position does not significantly influence testosterone concentrations and anogenital distance of fetuses. In comparison, administration of testosterone propionate to pregnant females, at doses that doubled fetal female testosterone levels, did masculinize the reproductive system. Discovery of androgen-active chemicals in the environment has placed increased emphasis on describing the reproductive and behavioral effects of both natural and environmental androgens and antiandrogens. Recently, the effects of an antiandrogen, vinclozolin, on the brain and behavior were cited as a special concern by the U.S. Environmental Protection Agency in its risk assessment of this pesticide. In rats, one such behavior that is perinatally organized by androgens is social play. Males play more than females, and administration of exogenous androgens during the neonatal period alters the juvenile expression of this sexually dimorphic behavior. Vinclozolin is an androgen receptor antagonist that inhibits androgen-dependent tissue growth in vivo. We were interested in whether developmental exposure to vinclozolin could also alter androgen-dependent behaviors such as play. Neonatal male rats were injected on postnatal days (PNDs) 2 and 3 with corn oil, the pharmacologic antiandrogen flutamide (50 mg/kg), or vinclozolin (200 mg/kg). On PNDs 36-37 animals were observed for social play. Behaviors associated with general social activity such as sniffing and dorsal contact were unaffected by treatment. However, play behavior in males treated with flutamide or vinclozolin was significantly reduced, resembling levels of play characteristic of females rather than untreated males. Therefore, this study demonstrates that perinatal exposure to vinclozolin, an environmental antiandrogen, can alter androgen-dependent play behavior in the male rat.
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Written from the paper’s full text.
TL;DR
In Sprague-Dawley rats, neonatal exposure to the antiandrogens flutamide (50 mg/kg) or vinclozolin (200 mg/kg) significantly reduced male rough-and-tumble play, making it resemble female levels, while general social behaviors were unaffected. The paper also reviews evidence that intrauterine position does not significantly affect fetal testosterone or anogenital distance in this rat strain and proposes play as an androgen-organized assay for endocrine disruptors.
Key findings
- Neonatal male rats injected on postnatal days (PNDs) 2 and 3 with corn oil, flutamide (50 mg/kg), or vinclozolin (200 mg/kg) showed significantly reduced play behavior on PNDs 36–37 after flutamide or vinclozolin, resembling female levels; sniffing and dorsal contact were unaffected.
- In related work (Hotchkiss et al. 2001), female pups treated with testosterone propionate showed increased rough-and-tumble play without altered other social activities; males treated with flutamide (50 mg/kg/day) or vinclozolin (200 mg/kg/day) showed decreased play bouts.
- In CD-SD Charles River rats, intrauterine position did not significantly influence fetal testosterone concentrations or anogenital distance; testosterone propionate to pregnant females at doses that doubled fetal female testosterone levels masculinized the reproductive system.
- Vinclozolin is an androgen receptor antagonist; the U.S. EPA cited its effects on brain and behavior as a special concern in vinclozolin risk assessment.
Methods
- The paper combines a review with original neonatal rat experiments in Sprague-Dawley/CD-SD Charles River rats.
- Neonatal male rats were injected on PNDs 2 and 3 with corn oil, flutamide (50 mg/kg), or vinclozolin (200 mg/kg); social play was observed on PNDs 36–37. In a related study, female pups received corn oil or testosterone propionate (250 g/kg/day as stated) on PNDs 2 and 3; males received corn oil, flutamide (50 mg/kg/day), or vinclozolin (200 mg/kg/day); play was observed for pairs of same litter, sex, and treatment for 10 min, with a play bout defined as one animal pinned to the floor with another on top.
- Analyses compared frequencies of social behaviors (e.g., sniffing, dorsal contact, rough-and-tumble play) and sex differences; intrauterine position effects were examined on testosterone concentrations in fetal carcass, reproductive tract, and amniotic fluid and on anogenital distance.
Limitations
- Stated: the neonatal rodent subcutaneous injection route has limited applicability to primates; because CNS development timing differs, none of the standard routes (lactational, gavage, subcutaneous) precisely simulates human exposure. The paper calls for studies measuring active vinclozolin metabolites in the rat CNS during neonatal life and comparing them with primate transplacental exposures.
- Stated: intrauterine position findings in rats are inconsistent, and one study estimated that intrauterine position explained less than 12% of variation in prenatal testosterone; effects may be subtle and easily overshadowed.
- Stated/evident: protocol differences (lactational vs direct pup exposure, dose, and lighting during testing) may explain contradictory vinclozolin play results across studies; the text also notes some cited findings are from an abstract/unpublished data.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
4 of 84 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured
- Premisecitation§ Natural Variation in Androgen Concentrations during Development
In one study, the amount of variation in prenatal testosterone explained by intrauterine position was estimated to be less than 12%.
“In addition, in one study the amount of variation in prenatal testosterone, which was explained by the IUP, was estimated to be less than 12% (Houtsmuller et al. 1995).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Houtsmuller et al. 1995 source
The Discussion reports that the number of caudal males explained about 12% of the variation in testosterone among female rat fetuses on day 19 of gestation. The claim captures the small contribution of intrauterine position, but states it as less than 12% and omits the study’s restriction to female rat fetuses and caudal males. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation§ Natural Variation in Androgen Concentrations during Development
Even during the critical window, developing female fetuses have significant testosterone concentrations in many tissues, including those critical for the developing reproductive system.
“However, even during this critical window, developing female fetuses have significant testosterone concentrations in many differ- ent tissues, including those critical for the developing reproductive system (Baum et al. 1991; Houtsmuller et al. 1995; Weisz and Ward 1980).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites Baum et al. 1991
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Houtsmuller et al. 1995 source
Table 1 (p. 496) reports measurable plasma testosterone in female rat fetuses on day 19 of gestation, within the critical window described in the Introduction. The Hormone Measurements section says testosterone was measured in plasma; the paper does not establish concentrations in many tissues, including reproductive tissues. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites Weisz and Ward 1980 source
- Findingown data§ Abstract
Administration of testosterone propionate to pregnant females at doses that doubled fetal female testosterone levels masculinized the reproductive system.
“In comparison, administration of testosterone propionate to pregnant females, at doses that doubled fetal female testosterone levels, did masculinize the reproductive system.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
In CD-SD Charles River rats, intrauterine position does not significantly influence fetal anogenital distance.
“However, in our strain of rat (CD-SD Charles River), intrauterine position does not significantly influence testosterone concentrations and anogenital distance of fetuses.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
In CD-SD Charles River rats, intrauterine position does not significantly influence fetal testosterone concentrations.
“However, in our strain of rat (CD-SD Charles River), intrauterine position does not significantly influence testosterone concentrations and anogenital distance of fetuses.”
Quote in the paperSubstantial claim
- Findingown data§ Abstract
Neonatal male rats treated with flutamide (50 mg/kg) on postnatal days 2 and 3 show significantly reduced play behavior compared with controls.
“However, play behavior in males treated with flutamide or vinclozolin was significantly reduced, resembling levels of play characteristic of females rather than untreated males.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Neonatal male rats treated with vinclozolin (200 mg/kg) on postnatal days 2 and 3 show significantly reduced play behavior compared with controls.
“However, play behavior in males treated with flutamide or vinclozolin was significantly reduced, resembling levels of play characteristic of females rather than untreated males.”
Quote in the paperSubstantial claim - Findingnone given§ Summary
Results of current studies of IUP effects in the Sprague-Dawley rat suggest that IUP is not a significant source of variability in terms of testosterone and masculinization.
“results of current studies of IUP effects in the Sprague-Dawley rat suggest that it is not a significant source of variability in terms of testosterone and mas- culinization.”
Quote in the paperNot a substantial claim - Premiseown data§ Abstract
Exposure to exogenous androgens permanently masculinizes females.
“Male fetuses exposed to antiandrogens during perinatal life are permanently demasculinized in their morphology and physiology, whereas exposure to exogenous androgens permanently masculinizes females.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ Abstract
In mammals, exposure to androgens early in development is essential for masculinization of the male reproductive phenotype.
“In mammals, exposure to androgens early in development is essential for masculinization of the male reproductive phenotype.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jost 1953
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Abstract
Male rats play more than female rats.
“Males play more than females, and administration of exogenous androgens during the neonatal period alters the juvenile expression of this sexually dimorphic behavior.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hotchkiss et al. 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Abstract
In rats, social play is perinatally organized by androgens.
“In rats, one such behavior that is perinatally organized by androgens is social play.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ Abstract
Male fetuses exposed to antiandrogens during perinatal life are permanently demasculinized in their morphology and physiology.
“Male fetuses exposed to antiandrogens during perinatal life are permanently demasculinized in their morphology and physiology, whereas exposure to exogenous androgens permanently masculinizes females.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Gray et al. 1994 source
- cites Wolf et al. 2000
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Natural Variation in Androgen Concentrations during Development
2M female rodents show masculinized sexually dimorphic structures including anogenital distance and the sexually dimorphic preoptic area of the brain.
“In accordance with effects of prenatal testosterone, 2M female rodents show mas- culinized sexually dimorphic structures including the AGD and the sexually dimor- phic preoptic area of the brain (Clark et al. 1993; Vandenbergh and Huggett 1995; vom Saal et al. 1999).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Clark et al. 1993 source
- cites Vandenbergh and Huggett 1995
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites vom Saal et al. 1999
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Role of Androgens in Reproductive and Behavioral Development
In some species of mammals, conversion of testosterone into estradiol by aromatase in the brain is critical for organization of the male phenotype.
“In some species of mammals, the conver- sion of testosterone into estradiol by aro- matase in the brain is critical for the organization of the male phenotype.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Paup et al. 1972
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Role of Androgens in Reproductive and Behavioral Development
Females exposed to androgens during the appropriate perinatal period can be masculinized in morphology, physiology, and behavior.
“Whereas perinatal exposure to androgens is essential for masculinization of males, numerous studies have shown that females exposed to androgens during the appropriate perinatal period can be masculinized in morphology, physiology, and behavior (Huffman and Hendricks 1981; Rhees et al. 1997; Thornton and Goy 1986; vom Saal 1979).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ Role of Androgens in Reproductive and Behavioral Development
In the rat, differentiation of the male reproductive phenotype depends on both Mullerian-inhibiting substance and testosterone.
“In the rat, differentiation of the male reproductive phenotype depends on both Mullerian-inhibiting substance (MIS) and testosterone.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jost 1953
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Role of Androgens in Reproductive and Behavioral Development
Behaviorally, hormones act prenatally to organize neural systems that later can be activated by the same steroid hormones and elicit behavior.
“Behaviorally, hormones act prenatally to organize neural systems that later can be acti- vated by the same steroid hormones and elicit behavior (Phoenix et al. 1959).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Phoenix et al. 1959
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning§ Role of Androgens in Reproductive and Behavioral Development
The brain of the male rat is masculinized primarily by estradiol from the aromatization of testosterone.
“Together, these studies sug- gest that the brain of the male rat is masculin- ized primarily by estradiol from the aromatization of testosterone.”
Quote in the paperSubstantial claim - Premisecitation§ Natural Variation in Androgen Concentrations during Development
In that study, no correlation was found between masculinization due to intrauterine position and increasing anogenital distance.
“Furthermore, no correlation was found between masculiniza- tion due to IUP and increasing AGD.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hotchkiss et al. 2000
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Natural Variation in Androgen Concentrations during Development
In these litter-bearing species, the sex of neighboring fetuses affects exposure to androgens and estradiol of the developing fetus.
“In these two species, the sex of the neighboring fetuses affects exposure to androgens and estradiol of the developing fetus (Clark et al. 1991; vom Saal and Bronson 1980).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ Natural Variation in Androgen Concentrations during Development
In fetal rats, males and females have similar androgen content during much of gestation.
“Quantitative examination of androgens in fetal rats shows that males and females have similar androgen content during much of gestation (Baum et al. 1991; Weisz and Ward 1980).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Baum et al. 1991
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Weisz and Ward 1980 source
- Premisecitation§ Role of Androgens in Reproductive and Behavioral Development
Inhibition of aromatase activity by pharmacologic antagonists feminizes sexual behavior of male rats.
“Inhibition of aromatase activity by pharmacologic antagonists feminizes sexual behavior of male rats (Gladue and Clemens 1980; McEwen 1981).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ Role of Androgens in Reproductive and Behavioral Development
In the rat, many organizing effects of testosterone can be induced by administration of estradiol.
“For example, in the rat many of the organizing effects of testosterone also can be induced by administration of estradiol (Paup et al. 1972).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Paup et al. 1972
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Natural Variation in Androgen Concentrations during Development
Female rodents that develop between two males (2M) are exposed to higher levels of androgens than females that develop between two females (0M).
“Females that develop between two males (2M females) are exposed to higher levels of androgens than females that develop between two females (0M females).”
Quote in the paperSubstantial claim - Premisecitation§ Effect of Androgen-Active Chemicals on Behavior
Some behaviors, such as rough-and-tumble play, are specifically organized by androgens.
“However, some behaviors, such as rough-and-tumble play, are specifi- cally organized by androgens.”
Quote in the paperSubstantial claim - Premisecitation§ Role of Androgens in Reproductive and Behavioral Development
Play is organized by the perinatal interaction of androgens with the androgen receptor.
“Play is organized by the peri- natal interaction of androgens with the AR (Meaney et al. 1983; Meaney and McEwen 1986; Pellis and Pellis 1997).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ Natural Variation in Androgen Concentrations during Development
In the rat, consistent effects due to intrauterine position on testosterone concentrations, and therefore potential interactions with EDCs, have not been found.
“In the rat, consistent effects due to IUP on testosterone concentrations, and therefore potential interactions with EDCs, have not been found.”
Quote in the paperNot a substantial claim - Premisecitation§ Natural Variation in Androgen Concentrations during Development
In several cases, individual female concentrations of testosterone are within the range experienced by males.
“In several cases, individual female concentrations of testosterone are within the range experienced by males (Hotchkiss et al. 2000; Weisz and Ward 1980).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Hotchkiss et al. 2000
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Weisz and Ward 1980 source
- Interpretationown data§ Abstract
Perinatal exposure to vinclozolin, an environmental antiandrogen, can alter androgen-dependent play behavior in the male rat.
“Therefore, this study demonstrates that perinatal exposure to vinclozolin, an environmental antiandrogen, can alter androgen-dependent play behavior in the male rat.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
Administration of exogenous androgens during the neonatal period alters the juvenile expression of sexually dimorphic play behavior in rats.
“Males play more than females, and administration of exogenous androgens during the neonatal period alters the juvenile expression of this sexually dimorphic behavior.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Meaney and Stewart 1981
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Natural Variation in Androgen Concentrations during Development
In a recent study with Sprague-Dawley rats, no effect of either contiguous or caudal intrauterine position on testosterone concentration was detected in fetal carcass, reproductive tract, or amniotic fluid.
“No effect of either contiguous or caudal IUP on testosterone concentration was detected in fetal carcass, reproductive tract, or amniotic fluid.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hotchkiss et al. 2000
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Role of Androgens in Reproductive and Behavioral Development
Testosterone, reduced by 5 reductase to dihydrotestosterone, is important for development of external genitalia and the prostate.
“Testosterone, reduced by the enzyme 5 reductase to dihydrotestosterone, is impor- tant for development of external genitalia and the prostate (Wilson and Lasnitzki 1971).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wilson and Lasnitzki 1971 source
- Interpretationreasoning§ Effect of Androgen-Active Chemicals on Behavior
Play behavior provides a straightforward rodent model for the effects of environmental chemicals on androgen-organized development.
“Therefore, play behavior provides a straightforward rodent model for the effects of environmental chemicals on androgen- organized development.”
Quote in the paperSubstantial claim- Rests on an assumption: Few studies have used play as a behavioral assay for androgen-active environmental chemicals.
- Premisecitation§ Effect of Androgen-Active Chemicals on Behavior
Administration of estradiol agonists does not increase play in either male or female rats.
“Further, androgen receptor dysfunctions such as testicular femi- nized mutant males, neonatal castration, and neonatal exposure to the androgen-receptor antagonist flutamide decrease the expression of play by juvenile males, whereas adminis- tration of estradiol agonists does not increase play in either male or female rats (Meaney and Stewart 1981).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Meaney and Stewart 1981
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Summary
These biomarkers include the androgen-sensitive AGD and areola/nipple formation.
“These biomarkers include the androgen-sensitive AGD and areola/nipple formation.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
Much of sexual differentiation of the brain in rats occurs during the first several days postpartum.
“Much of sexual differentiation of the brain in rats occurs during the first several days postpartum (Tobet et al. 1982).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tobet et al. 1982 source
- Interpretationreasoning§ Discussion
Subcutaneous and oral routes of administration are likely to provide similar internal exposures.
“Hence, subcutaneous and oral routes of administration are likely to provide simi- lar internal exposures.”
Quote in the paperNot a substantial claim - Interpretationcitation§ Effect of Androgen-Active Chemicals on Behavior
Results of the androgen and androgen-receptor antagonist experiments support rough-and-tumble play as a neonatally androgen-organized behavior.
“Together, results of the androgen and androgen-receptor antagonist experi- ments support rough-and-tumble play as a neonatally androgen-organized behavior.”
Quote in the paperSubstantial claim - Premisecitation§ Effect of Androgen-Active Chemicals on Behavior
Androgen receptor dysfunctions such as testicular feminized mutant males, neonatal castration, and neonatal exposure to the androgen-receptor antagonist flutamide decrease the expression of play by juvenile males.
“Further, androgen receptor dysfunctions such as testicular femi- nized mutant males, neonatal castration, and neonatal exposure to the androgen-receptor antagonist flutamide decrease the expression of play by juvenile males, whereas adminis- tration of estradiol agonists does not increase play in either male or female rats (Meaney and Stewart 1981).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Meaney and Stewart 1981
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Effect of Androgen-Active Chemicals on Behavior
In that study, exposure to the fungicide vinclozolin decreased play behavior in an antiandrogenic manner.
“Exposure to the fungicide vinclozolin also decreased play behavior in an antiandrogenic manner.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hotchkiss et al. 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning§ Effect of Androgen-Active Chemicals on Behavior
Differences in protocol between studies could explain inconsistencies in results on vinclozolin effects on play.
“However, differences in protocol between these studies could explain inconsistencies in results.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Discussion
None of the standard routes of exposure (lactational, gavage, subcutaneous injection) simulates precisely what might occur in humans.
“However, because of species differences in the rates of CNS development in relation to the timing of birth, none of the standard routes of expo- sure (lactational, gavage, subcutaneous injection) simulates precisely what might occur in humans.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Summary
Play behavior provides a straightforward rodent model for assessing the effects of environmental chemicals on AR-organized development.
“Play behavior provides a straight- forward rodent model for assessing the effects of environmental chemicals on AR-organized development.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
In primates, much of sexual differentiation of the brain occurs in utero.
“By compar- ison, in primates much of this differentia- tion occurs in utero (Cooke et al. 1998).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cooke et al. 1998 source
- Interpretationcitation§ Discussion
Neonatal rat administration of vinclozolin likely would be easily absorbed because of the immature status of the gastrointestinal tract at this age.
“Further, neonatal rat admin- istration of vinclozolin likely would be easily absorbed because of the immature status of the gastrointestinal tract at this age (Klein 1986).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Klein 1986 source
- Premisecitation§ Effect of Androgen-Active Chemicals on Behavior
In that study, the AR antagonist flutamide significantly decreased the number of play bouts observed in males.
“In males, the AR antagonist flutamide significantly decreased the number of play bouts observed.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hotchkiss et al. 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Effect of Androgen-Active Chemicals on Behavior
Neonatal exposure to testosterone increased play in juvenile female rats.
“Although Meaney and Stewart (1981) showed that neonatal exposure to testosterone increased play in juvenile female rats, few studies have used play as a behavioral assay for androgen-active environmental chemi- cals.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Meaney and Stewart 1981
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ Effect of Androgen-Active Chemicals on Behavior
In a recent study, a significant sex difference in play behavior between male and female juvenile rats was observed.
“Overall, a significant sex difference in play behavior between male and female juve- nile rats was observed (Hotchkiss et al. 2001).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hotchkiss et al. 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Classified as probably not a substantial claim. 19
- The quote only partly states this claim. 1
- May combine two claims. 15
Classified as probably not a substantial claim.
Premisecitation§ DiscussionRecent reports have identified androgenic chemicals in the environment.
“In addition, recent reports (Gray et al. 2001b; Parks et al. 2001; Schiffer et al. 2001) of androgenic chemicals in the environment necessitate development of behavioral tests for assess- ing organizational effects of these chemicals on females.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Gray et al. 2001b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Parks et al. 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Schiffer et al. 2001 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionA cohort of women between 20 and 40 years of age had measurable amounts of endocrine-active chemicals in their urine.
“Blount et al. (2000) showed that a cohort of women between 20 and 40 years of age had measurable amounts of endocrine-active chemicals in their urine.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Blount et al. (2000) source
The quote only partly states this claim.
Findingown data§ AbstractBehaviors associated with general social activity such as sniffing and dorsal contact were unaffected by treatment with flutamide or vinclozolin.
“Behaviors associated with general social activity such as sniffing and dorsal contact were unaffected by treatment.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ AbstractIn some litter-bearing species, proximity in utero of females to males can partially masculinize female siblings and alter their responsiveness to endocrine-disrupting compounds.
“In some litter-bearing species, proximity in utero of females to males can partially masculinize female siblings and alter their responsiveness to endocrine-disrupting compounds.”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone given§ Effect of Androgen-Active Chemicals on BehaviorIn rodents, many behaviors are masculinized by the conversion of testosterone into estradiol in the brain.
“In rodents, many behaviors are masculinized by the conversion of testosterone into estra- diol in the brain.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Natural Variation in Androgen Concentrations during DevelopmentIn both gerbils and mice, intrauterine position of females has significant influence on subsequent litter sex ratios.
“Interestingly, in both gerbils and mice, the intrauterine position of females has signifi- cant influence on their subsequent litter sex ratios.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Clark and Galef 1995 source
- cites Vandenbergh and Huggett 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ Role of Androgens in Reproductive and Behavioral DevelopmentTestosterone is important for differentiation of the Wolffian ducts, associated sex accessory tissues, and testicular descent.
“Whereas MIS is critical for the inhibition of the Mullerian system, testosterone is important for differenti- ation of the Wolffian ducts, associated sex accessory tissues, and testicular descent (Jost 1970).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jost 1970 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Natural Variation in Androgen Concentrations during DevelopmentBrief exposure to elevated androgens late in gestation sensitizes the developing male to androgen exposure during the neonatal period.
“Several studies have suggested that this brief expo- sure to elevated androgens late in gestation sensitizes the developing male to androgen exposure during the neonatal period (Baum et al. 1990; Hoepfner and Ward 1988; Tobet and Baum 1987).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone given§ Natural Variation in Androgen Concentrations during DevelopmentIn several other litter-bearing species, variation in prenatal androgens can be largely attributed to the intrauterine position phenomenon.
“In several other litter-bearing species, vari- ation in prenatal androgens can be largely attributed to the intrauterine position (IUP) phenomenon.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Effect of Androgen-Active Chemicals on BehaviorThe critical time in the rat for organization of play is the early neonatal period, when interactions of androgens with the androgen receptor set up the sex difference observed in juveniles.
“The critical time in the rat for organization of play is the early neonatal period, when interactions of androgens with the AR set up the sex differ- ence observed in juveniles (Meaney et al. 1983; Meaney and McEwen 1986; Pellis and Pellis 1997).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Meaney et al. 1983
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Meaney and McEwen 1986 source
- cites Pellis and Pellis 1997
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ AbstractVinclozolin is an androgen receptor antagonist that inhibits androgen-dependent tissue growth in vivo.
“Vinclozolin is an androgen receptor antagonist that inhibits androgen-dependent tissue growth in vivo.”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ Natural Variation in Androgen Concentrations during DevelopmentFailure to account for intrauterine position in EDC toxicology studies could lead to false negative results, especially when adverse alterations are produced by low doses in fetuses from only one IUP.
“In this regard, failure to account for IUP in EDC toxicology studies could lead to false negative results, especially when adverse alterations are produced by low doses in fetuses from only one IUP (Howdeshell et al. 1999; Welshons et al. 1999).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Howdeshell et al. 1999 source
- cites Welshons et al. 1999
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Natural Variation in Androgen Concentrations during DevelopmentFemales that develop in utero between two males produce more males in their litters than do females gestated between two females.
“Females that develop in utero between two males produce more males in their litters than do females gestated between two females (Clark and Galef 1995; Vandenbergh and Huggett 1994).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Clark and Galef 1995 source
- cites Vandenbergh and Huggett 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Premisecitation§ SummarySeveral useful biomarkers have been suggested for characterizing the prenatal androgen environment.
“Regardless of the sources of variation in prenatal androgens, several use- ful biomarkers have been suggested for char- acterizing the prenatal androgen environment (Gray et al. 1999; Vandenbergh and Huggett 1995).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Gray et al. 1999
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Vandenbergh and Huggett 1995
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ SummaryDiscovery of novel antiandrogens and reports of androgenic chemicals in the environment has renewed interest in describing the role of androgens in reproductive and behavioral development.
“Discovery of novel antiandrogens (Mylchreest et al. 1998; Parks et al. 2000) and reports of androgenic chemicals (Gray et al. 2001a; Parks et al. 2001; Schiffer et al. 2001) in the environment has renewed interest in describing the role of androgens in reproductive and behavioral develop- ment.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Mylchreest et al. 1998
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Parks et al. 2000
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Gray et al. 2001a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionA recent report by the U.S. Environmental Protection Agency calls for studies of the developmental neurotoxicity of vinclozolin.
“a recent report by the U.S. Environmental Protection Agency (U.S. EPA) calls for studies of the developmental neurotoxicity of vinclozolin (U.S. EPA 2000).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites U.S. EPA 2000
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ Effect of Androgen-Active Chemicals on BehaviorThe dose used in the Flynn study was lower (up to 60 mg/kg/day to pregnant female) than that used in the Hotchkiss et al. (200 mg/kg/day to neonatal pup) and Gray and Ostby studies (200 mg/kg/day to pregnant female).
“Second, the dose used in the Flynn study was lower (up to 60 mg/kg/day to pregnant female) than that used in the Hotchkiss et al. (200 mg/kg/day to neonatal pup) and Gray and Ostby studies (200 mg/kg/day to pregnant female).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone given§ DiscussionAntiandrogenicity of vinclozolin has been established since 1994.
“Although antiandrogenicity of vinclozolin has been established since 1994”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationcitation§ SummaryBoth of these indicators reflect the prenatal androgen environment and can be used for characterizing early developmental exposure to androgenic or antiandrogenic chemicals.
“Both of these indicators reflect the prenatal andro- gen environment and can be used for char- acterizing early developmental exposure to androgenic or antiandrogenic chemicals.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable). May combine two claims.
Interpretationreasoning§ DiscussionThis study has implications both for risk assessment of known antiandrogens, such as vinclozolin, and for testing of novel chemicals.
“This study has implications both for risk assessment of known antiandrogens, such as vinclozolin, and for testing of novel chemicals.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationnone given§ SummarySocial play is an androgen-organized behavior in rats that can be used to test for environmental androgens and antiandrogens.
“Finally, social play is an androgen- organized behavior in rats that can be used to test for environmental androgens and antiandrogens.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Effect of Androgen-Active Chemicals on BehaviorIn studies by Flynn et al. (2001) and Gray and Ostby (1998), neonatal exposure to the AR antagonist was through lactational exposure, whereas in Hotchkiss et al. (2001) the compound was administered directly to the pup.
“First, in studies conducted by Flynn et al. (2001) and Gray and Ostby (1998), neonatal exposure to the AR antagonist was through lactational exposure. In the Hotchkiss et al. study (2001), the compound was administered directly to the pup.”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone given§ SummaryIUP has been shown to explain much of the variability in prenatal androgens in the mouse and gerbil.
“Although IUP has been shown to explain much of the variability in prenatal androgens in the mouse and gerbil”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Interpretationreasoning§ DiscussionIf concentrations of active metabolites are comparable between these species, then injections of endocrine-active chemicals into neonatal rats could constitute a meaningful route of exposure at the appropriate developmental period.
“If concentrations of active metabolites are comparable between these species, then injections of endocrine- active chemicals into neonatal rats could constitute a meaningful route of exposure at the appropriate developmental period.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).
Interpretationnone given§ DiscussionThis lag in behavioral data on vinclozolin likely results from the limited numbers of behaviors masculinized by androgens, rather than estradiol, in the rodent.
“This lag in behavioral data on vinclozolin likely results from the limited numbers of behaviors masculinized by androgens, rather than estradiol, in the rodent.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Effect of Androgen-Active Chemicals on BehaviorIn both Flynn et al. (2001) and Gray and Ostby (1998) studies, no effect of perinatal vinclozolin was found on male play behavior.
“In both of these studies, no effect of perinatal vinclo- zolin was found on male play behavior.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Effect of Androgen-Active Chemicals on BehaviorIn that study, females treated with testosterone propionate had increased levels of rough-and-tumble play without alteration in the frequency of other social activities.
“Females treated with testosterone pro- pionate had increased levels of rough-and- tumble play without alteration in the frequency of other social activities.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hotchkiss et al. 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationreasoning§ DiscussionPlay behavior could be developed into a rodent behavioral test for chemicals with androgenic or antiandrogenic activity.
“Considering the utility of this assay for testing behavioral effects of these EDCs, play behavior could be developed into a rodent behavioral test for chemicals with androgenic or antiandrogenic activity.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Effect of Androgen-Active Chemicals on BehaviorThe two other studies observed higher levels of play behaviors in males than in females during lights out when activity levels are higher in nocturnal animals such as the rat.
“This is in contrast to the two other studies that observed higher levels of play behaviors in males than in females during lights out when activity levels are higher in nocturnal animals such as the rat.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationcitation§ Effect of Androgen-Active Chemicals on BehaviorRat rough-and-tumble play is clearly organized by androgens themselves during the neonatal period and is not influenced by activational effects of other steroid hormones.
“Therefore, rat rough-and- tumble play is unique in that it is clearly organized by androgens themselves during the neonatal period and is not influenced by activational effects of other steroid hormones.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Few studies have used play as a behavioral assay for androgen-active environmental chemicals.
“Although Meaney and Stewart (1981) showed that neonatal exposure to testosterone increased play in juvenile female rats, few studies have used play as a behavioral assay for androgen-active environmental chemi- cals.”
The paper relies on this without support.
Toxicants present in pregnant females can be transferred to their offspring.
“Therefore, toxicants present in pregnant females potentially could be transferred to their offspring.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rat example cites a hamster study
MinorThe text presents Paup et al. (1972) as an example concerning rats, but the paper's reference list identifies that study as being about female golden hamsters.
“For example, in the rat many of the organizing effects of testosterone also can be induced by administration of estradiol (Paup et al. 1972).”
“Paup DC, Coniglio LP, Clemens LG. 1972. Masculinization of the female golden hamster by neonatal treatment with androgen or 17 estradiol.”
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BackgroundInfluentialA gerbil dam's fetal intrauterine position affects the sex ratios of litters she gestates
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Self-citation
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Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease
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Epigenetic Transgenerational Actions of Endocrine Disruptors
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“A commonly used antiandrogenic endocrine disruptor is vinclozolin, which is used as a fungicide in the wine industry (102, 103).”
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Epigenetic transgenerational actions of endocrine disruptors
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The role of animal behaviour in the study of endocrine-disrupting chemicals
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“Experimental designs that are commonly used in behavioural ecology, and increasingly in ecotoxicology, include using individuals as their own ANIMAL BEHAVIOUR, --, -470 REVIEW 471 Table (continued) Behavioural effect Taxa Endocrine disrupter References Increased female reproductive behaviour Rat o,p0-DDT Etgen 1982 In…”
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“…prostate weight, reduced testis and epididymal weights, and altered behavior in male offspring (Foster and McIntyre 2002; Gray et al. 1994; Hellwig et al. 2000; Hib and Ponzio 1995; Hotchkiss et al. 2002; McIntyre et al. 2001; Miyata et al. 2002; Ostby et al. 1999; Shimamura et al. 2002).”
BackgroundResultKodavanti, P. R. S., Coburn, C. G., MOSER, V. C., MacPhail, R. C., Fenton, S. E., Stoker, T. E., Rayner, J. L., Kannan, K., & Birnbaum, L. S. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq105 · Cited by 194 · see citing works
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“Embryonic exposure to vinclozolin has been documented to influence sexual differentiation, gonadal formation, and reproductive functions in the exposed F1 generation as they develop and mature (Kelce et al. 1994, Gray et al. 1999, Wolf et al. 2000, Hotchkiss et al. 2002, Uzumcu et al. 2004).”
BackgroundA Case for Revisiting the Safety of Pesticides: A Closer Look at Neurodevelopment
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“The most vulnerable target was the hippocampus, with the damage expressed both as deficits in nerve activity and as corresponding behavioral abnormalities (Icenogle et al. 2004).”
BackgroundCurrent concepts in neuroendocrine disruption
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“The traits most affected by VIN include sociosexual, anxiety, cognition, appetitive, and locomotor behaviors.”
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Perinatal Exposure to the Fungicide Prochloraz Feminizes the Male Rat Offspring
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“The conversion of testosterone into estradiol by aromatase in the brain, however, is critical for the organization of the male brain in rats (Hotchkiss et al., 2002).”
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“Different aspects of social behavior are impaired in laboratory rodents exposed to diverse EDCs including PCBs [16], BPA [17, 18], mercury, cadmium [19], and vinclozolin [20], among others [21].”
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“In female fetuses, however, testosterone is produced by gonads as well as placenta and/or fetal adrenals, and its plasma concentrations remain constantly elevated throughout gestation[143].”
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“Common developmental effects of all three single chemicals after perinatal exposure ofmale rats include alteredAGD, nipple retention (NR), hypospadias, reduced reproductive organ weights, and altered behavior in male offspring (Foster and McIntyre, 2002; Gray et al., 1994; Hellwig et al., 2000; Hib and Ponzio, 1995; H…”
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An environmental antiandrogen, vinclozolin, alters the organization of play behavior
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“3. In the rat, sexual differentiation of the reproductive tract is perinatal, whereas central nervous system (CNS) sexual differentiation is a postnatal event, regulated to a great degree by aromatization of testosterone to estradiol (play behavior, an exception, is androgen dependent in both rats [ Hotchkiss et al. 2…”
BackgroundSelf-citationMaternal exposure to butyl paraben impairs testicular structure and sperm quality on male rats
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“Because perinatal exposure to androgens has lasting effects on the physiology of the adult animal (Hotchkiss et al., 2002), we evaluated the sexual behavior of male offspring maternally exposed to BP.”
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“In contrast, the existing dogma regarding the critical period for sex differences in rough-and-tumble play behaviors is that differentiation takes place exclusively during early postnatal development [2,3].”
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“For example, in the case of chemicals that affect androgen action, extensive information known about the regulation of male sexual differentiation by androgens across vertebrates (Hotchkiss et al., 2002; Wilson et al., 2004, 2007; Hartig et al., 2007) would be part of the weight-ofevidence that, combined with gene, pa…”
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“Exposure to anti-androgens de-masculanizes the male fetus resulting in a variety of morphological and physiological alterations (Hotchkiss et al., 2002).”
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Endocrine-Disrupting Chemicals
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“However, there are limitations in the use of these anti-androgen medications, especially in patients who are pregnant or hoping to become pregnant as there may be an increased risk of feminization of a male fetus, thus necessitating other therapeutic options that can achieve similar anti-androgenic effects [39].”
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“Testosterone can also cause masculinization to arise in mammals [21,22].”
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“Studies in rats demonstrate the ability of vinclozolin to alter many hormonally regulated behaviors including play behavior (Colbert et al., 2005; Hotchkiss et al., 2002), learning (André and Markowski, 2006), locomotor activity (Flynn et al.”
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“In animal experiments, PAEs have been shown to decrease T and LH and increase FSH (Hotchkiss et al. 2002) and they can also induce infertility in men (Christiansen et al. 2010).”
BackgroundInfluentialBiosensors for endocrine disruptors
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“These EDCs have been found in human blood and breast milk, in marine mammals, and in marine and freshwater fish; and their levels are continuously increasing (Guillette et al. 1994; Hotchkiss et al. 2002).”
BackgroundLaser and Light-Based Therapies for Hirsutism Management in Women With Polycystic Ovarian Syndrome
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“…ピークがみられた。これらの結果は,メ チルパラチオンに対 する皮膚や胎盤の防御機構が脆弱であることを示唆している。 パラチオン,ク ロルピリホスおよびダイアジノンの新生仔 ラッ トにおける神経伸長およびコリン作動性ニューロンへの 影響を比較検討するとともに,こ れ ら化学物質の曝露による 致死性について検討 した報告がある(Slotkin et al.,2006)。 ラットに出生1~4日 にクロルピリホス,ダ イアジノンある いはパラチオンを皮下投与した。その結果,パ ラチオンによ る致死率(最 大耐用量:0.1mg/kg/day)は クロル ピリホス…”
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Safety evaluation of ondansetron after gestational exposure on male reproductive parameters in rats
Reis, A. C. C., Jorge, B. C., Stein, J., Moreira, S. D. S., Manoel, B. D. M., de Aquino, A. M., Valente, L. C., Kassuya, C. A. L., Scarano, W. R., & Arena, A. C. (2022) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2022.105302
- Authors
- Hotchkiss, A. K., Ostby, J. S., Vandenburgh, J. G., & Gray, L. E.
- Affiliations
- North Carolina State University (US)
- Venue
- Environmental Health Perspectives
- Publisher
- American Chemical Society (ACS)
- Published
- 2002-06-01
- Volume
- 110
- Issue
- suppl 3
- Pages
- 435-439
- ISSN
- 0091-6765 (ISSN-L)
- 1552-9924
- PMC
- PMC1241195
- OpenAlex
- W2038040689
- Semantic Scholar
- 1ba0f69bef50dcdb2c0d306ae3eff797d836ef47
- Cited by
- 82
- References
- 60
- Citations by year
- 2024: 2 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 5 · 2012: 3
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/licenses/by/4.0/ (vor, 5690 d)
- Locations
- Environmental Health Perspectives (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Reproductive biology and impacts on aquatic species
- Keywords
- androgens, androgen receptor antagonists, vinclozolin, flutamide, social play, masculinization, perinatal exposure, prenatal androgen exposure, sexual differentiation, reproductive development, anogenital distance, endocrine disruptors, Sprague-Dawley rats
- MeSH terms
- Androgen Antagonists, Androgens, Animals, Animals, Newborn, Environmental Exposure, Female, Gonads, Male, Oxazoles, Play and Playthings, Reproduction, Social Behavior, Rats, Sprague-Dawley, Risk Assessment, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-12.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-12.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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