Effects of in utero and lactational exposure to tamoxifen in SD rats

Yamasaki, Kanji; Noda, Shuji; Muroi, Takako; Mitoma, Hideo; Takakura, Saori; Sakamoto, Satoko

doi:10.1016/j.toxlet.2004.12.001

Cited by 9 publications

(3 citation statements)

References 26 publications

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“…From these results, since any endocrine disrupting activity of lindane is clearly weak, adverse effects might not have been expected in this study. A large number of investigations have shown effects of endocrine disruptors detected by examining AGD, nipple development, sexual maturation, estrous cycle, spermatogenesis, and sex organ weights (Aoyama and Suzuki, 2003;You et al, 2002;Ashby et al, 1997;Sharpe et al, 1995;Newbold et al, 1983;Yamasaki et al, 2005;Chamness et al, 1979;Clevenger et al, 1998;Gray et al, 1993Gray et al, , 1994Goldman et al, 1976;Rhees et al, 1997). Therefore, further studies using other chemicals, which have more definite endocrine disrupting activity, are considered necessary to establish the validity of the new protocol.…”

Section: Assessment Of the Test Methodsmentioning

confidence: 99%

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

et al. 2005

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-A two-generation reproduction toxicity study in rats adding extra endpoints to detect endocrine disrupting activity was conducted using lindane by dietary administration at 0, 10, 60, and 300 ppm, for investigation of its utility. The extra endpoints included anogenital distance (AGD), nipple development, sexual maturation (vaginal opening and preputial separation), estrous cycle, spermatogenesis, sex organ weights, and blood hormone concentrations (thyroid and sex hormones). F1 offspring were examined for emotionality (open field test), motor coordination (rotarod test), as well as learning and memory (pole-climbing test). Hepatic drug-metabolizing enzyme activities were also measured. The results revealed general toxicological effects on parental animals, influence on reproductive function, and altered development of offspring; however, they did not demonstrate any distinct changes in the extra endpoints for detection of endocrine disrupting activity. Adult toxicity was observed in both F0 and F1 animals, including suppressed body weight gain and reduced food consumption in both sexes, and deaths of females at 300 ppm. Convulsions and irritability were observed during the perinatal period in pregnant F1 females given 300 ppm. Pathological examination revealed increased liver weights and centrilobular hepatocellular hypertrophy in both sexes and generations at 10 or 60 ppm and above; in addition, increased kidney weights and increased hyaline droplets in the proximal tubule epithelium, and basophilic renal tubules in males were noted at 10 ppm and above. Pituitary weights were decreased in F0 females and in F1 males and females and adrenal weights were increased in F1 males and females at 300 ppm; however, no histological changes were observed, and manifestations suggesting endocrine disrupting activity related to these changes were lacking. Hypertrophy of the thyroid follicular epithelium in F0 females at 300 ppm and in F1 males at 60 and 300 ppm, and decreases in T3 and/or T4 in both sexes and generations at 300 ppm were presumed to be secondary changes associated with the induction of hepatic drug-metabolizing enzymes. Blood hormone analysis revealed no changes in sex hormones attributable to lindane in males or females. Hepatic drug-metabolizing enzyme activities were increased dose-dependently from 10 ppm in both sexes and generations, with the rise in BROD activity being the most prominent. There were also increases in MROD, EROD, T-6β-OH, and T4-UDP-GT activities (BROD >> EROD > MROD, T-6β-OH, T4-UDP-GT). This suggests that while lindane most strongly induces CYP2B, it also upregulates a number of other drug metabolizing enzymes, such as CYP1A, CYP3A, and UDP-GT. As for effects on reproductive function, lack of maternal behavior, including lactation and retrieval behavior, and consequent total litter loss were observed in F1 dams at 300 ppm. There were no effects of lindane on the estrous cycle, spermatogenesis, mating, fertility, pregnancy, or parturition. Neonatal toxicity was observed in bot...

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Section: Assessment Of the Test Methodsmentioning

confidence: 99%

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

et al. 2005

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“…There are three Col2-CreERT lines that differ by the different mutations in their ERT fusion protein and their sensitivity to tamoxifen (ERT in the line generated by Nakamura et al, (113) ER T2 in the line generated by Chen et al, (116) and the mouse ERTM in the line generated by Hilton et al (117) ). The sensitivity of these lines to tamoxifen should be taken into consideration, considering the toxicity of tamoxifen in embryos (221,222) and its effect on the adult skeleton. (223,224) There is also a Col2-CrertTa Tet ON line inducible upon doxycycline treatment.…”

Section: Cre Mice Targeting Chondrocytesmentioning

confidence: 99%

Sites of Cre-recombinase activity in mouse lines targeting skeletal cells

Couasnay

Madel

Lim

et al. 2020

Journal of Bone and Mineral Research

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The Cre/Lox system is a powerful tool in the biologist's toolbox, allowing loss-of-function and gain-of-function studies, as well as lineage tracing, through gene recombination in a tissue-specific and inducible manner. Evidence indicates, however, that Cre transgenic lines have a far more nuanced and broader pattern of Cre activity than initially thought, exhibiting "off-target" activity in tissues/cells other than the ones they were originally designed to target. With the goal of facilitating the comparison and selection of optimal Cre lines to be used for the study of gene function, we have summarized in a single manuscript the major sites and timing of Cre activity of the main Cre lines available to target bone mesenchymal stem cells, chondrocytes, osteoblasts, osteocytes, tenocytes, and osteoclasts, along with their reported sites of "off-target" Cre activity. We also discuss characteristics, advantages, and limitations of these Cre lines for users to avoid common risks related to overinterpretation or misinterpretation based on the assumption of strict cell-type specificity or unaccounted effect of the Cre transgene or Cre inducers.

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“…This research was conducted to examine the validity of the test method using the antiandrogenic substance vinclozolin; however, endocrine disrupting effects include estrogen effects, antiestrogen effects, and androgen effects in addition to antiandrogen effects. Although the mechanisms of action of endocrine disrupting effects differ, a large number of studies suggest that the effects can be detected by examining AGD, nipple development, sexual maturation, estrous cycle, spermatogenesis, and organ weights (Aoyama and Suzuki, 2003;You et al, 2002;Ashby et al, 1997;Sharpe et al, 1995;Newbold et al, 1983;Yamasaki et al, 2005;Chamness et al, 1979;Clevenger et al, 1998;Goldman et al, 1976;Rhees et al, 1997). Thus it can be expected that this study method is reliable for detecting endpoints considered to be useful for detection of endocrine disrupting effects other than antiandrogen influence.…”

Section: Assessment Of the Test Methodsmentioning

confidence: 97%

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Vinclozolin

et al. 2005

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-A two-generation reproduction toxicity study in rats adding extra endpoints to detect endocrine disrupting activity was conducted using vinclozolin by dietary administration at 0, 40, 200, and 1000 ppm, for investigation of its utility. The extra endpoints included anogenital distance (AGD), nipple development, sexual maturation (vaginal opening and preputial separation), estrous cycle, spermatogenesis, sex organ weights, and blood hormone concentrations (thyroid and sex hormones). Hepatic drugmetabolizing enzyme activities were also measured. The results revealed changes due to vinclozolin in the AGD, nipple development, sexual maturation, sex organ weights, and blood sex hormone concentrations in males of both parental animals and offspring, even at the lowest dose of 40 ppm, confirmed by results for the classical endpoints of histopathological examination at 200 ppm and mating at 1000 ppm. The effects on parental males included increased pituitary and testis weights, and decreased epididymis weights at 1000 ppm in both generations, and decreased prostate and epididymis weights at 200 and 1000 ppm and seminal vesicle weights at 1000 ppm in F1 males. Histopathological examination revealed hypertrophy of the basophilic cells in the pituitary at these two doses, and diffuse hyperplasia of the testicular interstitial cells and atrophy of the seminal vesicle mucosa at 1000 ppm in F0 and F1 males. In addition, F1 males demonstrated decrease in prostate fluid at 200 and 1000 ppm. Blood hormone analysis revealed increases in LH, FSH, testosterone, and DHT in F0 and F1 males at 1000 ppm. General toxicological effects included suppressed body weight gain in F0 and F1 females and in F1 males, and reduced food consumption in F0 and F1 females at 1000 ppm. Histopathological examination revealed centrilobular hepatocellular hypertrophy in males at 200 and 1000 ppm and in females at 1000 ppm, increased lipid droplets in the adrenal zona fasciculata and zona glomerulosa in males at 200 and 1000 ppm and in females at 40 ppm and above, and hyperplasia of ovarian interstitial cells and vacuolation of lutein cells in females at 1000 ppm in both generations. Almost all the tissue changes were accompanied by changes in weights. Decreases in T3 and/or T4 were observed in both sexes and generations at 1000 ppm and in F0 females at 200 ppm. However, these were presumed to be secondary to induction of hepatic drugmetabolizing enzymes, activities being increased for a range of enzymes in both sexes and generations at 1000 ppm. Rise in BROD activity was the most prominent, suggesting that vinclozolin mainly induces CYP2B. As for effects on reproductive function, a marked decrease in the fertility index caused by male infertility was observed in F1 animals at 1000 ppm. However, no effects on spermatogenesis were seen in either F0 or F1 males. Since cleft prepuce and penile hypoplasia were observed in infertile males, it is probable that the cause of infertility in F1 males was related to morphological abnormalities in the extern...

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Effects of in utero and lactational exposure to tamoxifen in SD rats

Cited by 9 publications

References 26 publications

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

Sites of Cre-recombinase activity in mouse lines targeting skeletal cells

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Vinclozolin

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