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Title: In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse

Abstract

Bisphenol A (BPA) is a known reproductive toxicant in rodents. However, the effects of in utero BPA exposure on early ovarian development and the consequences of such exposure on female reproduction in later reproductive life are unclear. Thus, we determined the effects of in utero BPA exposure during a critical developmental window on germ cell nest breakdown, a process required for establishment of the finite primordial follicle pool, and on female reproduction. Pregnant FVB mice (F0) were orally dosed daily with tocopherol-striped corn oil (vehicle), diethylstilbestrol (DES; 0.05 μg/kg, positive control), or BPA (0.5, 20, and 50 μg/kg) from gestational day 11 until birth. Ovarian morphology and gene expression profiles then were examined in F1 female offspring on postnatal day (PND) 4 and estrous cyclicity was examined daily after weaning for 30 days. F1 females were also subjected to breeding studies with untreated males at three to nine months. The results indicate that BPA inhibits germ cell nest breakdown via altering expression of selected apoptotic factors. BPA also significantly advances the age of first estrus, shortens the time that the females remain in estrus, and increases the time that the females remain in metestrus and diestrus compared to controls. Further,more » F1 females exposed to low doses of BPA exhibit various fertility problems and have a significantly higher percentage of dead pups compared to controls. These results indicate that in utero exposure to low doses of BPA during a critical ovarian developmental window interferes with early ovarian development and reduces fertility with age. - Highlights: • In utero BPA exposure inhibits germ cell nest breakdown in female mouse offspring. • In utero BPA exposure alters expression of apoptosis regulators in the ovaries of mouse offspring. • In utero BPA exposure advances first estrus age and alters cyclicity in mouse offspring. • In utero BPA exposure causes various fertility problems in female mouse offspring.« less

Authors:
; ;
Publication Date:
OSTI Identifier:
22439700
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 276; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; BREEDING; COMPARATIVE EVALUATIONS; CORN OIL; DOSES; FEMALES; FERTILITY; GENES; GERM CELLS; MICE; MORPHOLOGY; NESTS; OVARIES; PROGENY; REPRODUCTION; VITAMIN E

Citation Formats

Wang, Wei, E-mail: weiwang2@illinois.edu, Hafner, Katlyn S., E-mail: katlynhafner@gmail.com, and Flaws, Jodi A., E-mail: jflaws@illinois.edu. In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.02.009.
Wang, Wei, E-mail: weiwang2@illinois.edu, Hafner, Katlyn S., E-mail: katlynhafner@gmail.com, & Flaws, Jodi A., E-mail: jflaws@illinois.edu. In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse. United States. doi:10.1016/J.TAAP.2014.02.009.
Wang, Wei, E-mail: weiwang2@illinois.edu, Hafner, Katlyn S., E-mail: katlynhafner@gmail.com, and Flaws, Jodi A., E-mail: jflaws@illinois.edu. Tue . "In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse". United States. doi:10.1016/J.TAAP.2014.02.009.
@article{osti_22439700,
title = {In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse},
author = {Wang, Wei, E-mail: weiwang2@illinois.edu and Hafner, Katlyn S., E-mail: katlynhafner@gmail.com and Flaws, Jodi A., E-mail: jflaws@illinois.edu},
abstractNote = {Bisphenol A (BPA) is a known reproductive toxicant in rodents. However, the effects of in utero BPA exposure on early ovarian development and the consequences of such exposure on female reproduction in later reproductive life are unclear. Thus, we determined the effects of in utero BPA exposure during a critical developmental window on germ cell nest breakdown, a process required for establishment of the finite primordial follicle pool, and on female reproduction. Pregnant FVB mice (F0) were orally dosed daily with tocopherol-striped corn oil (vehicle), diethylstilbestrol (DES; 0.05 μg/kg, positive control), or BPA (0.5, 20, and 50 μg/kg) from gestational day 11 until birth. Ovarian morphology and gene expression profiles then were examined in F1 female offspring on postnatal day (PND) 4 and estrous cyclicity was examined daily after weaning for 30 days. F1 females were also subjected to breeding studies with untreated males at three to nine months. The results indicate that BPA inhibits germ cell nest breakdown via altering expression of selected apoptotic factors. BPA also significantly advances the age of first estrus, shortens the time that the females remain in estrus, and increases the time that the females remain in metestrus and diestrus compared to controls. Further, F1 females exposed to low doses of BPA exhibit various fertility problems and have a significantly higher percentage of dead pups compared to controls. These results indicate that in utero exposure to low doses of BPA during a critical ovarian developmental window interferes with early ovarian development and reduces fertility with age. - Highlights: • In utero BPA exposure inhibits germ cell nest breakdown in female mouse offspring. • In utero BPA exposure alters expression of apoptosis regulators in the ovaries of mouse offspring. • In utero BPA exposure advances first estrus age and alters cyclicity in mouse offspring. • In utero BPA exposure causes various fertility problems in female mouse offspring.},
doi = {10.1016/J.TAAP.2014.02.009},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 276,
place = {United States},
year = {Tue Apr 15 00:00:00 EDT 2014},
month = {Tue Apr 15 00:00:00 EDT 2014}
}
  • In utero bisphenol A (BPA) exposure affects reproductive function in the first generation (F1) of mice; however, not many studies have examined the reproductive effects of BPA exposure on subsequent generations. In this study, pregnant mice (F0) were orally dosed with vehicle, BPA (0.5, 20, and 50 μg/kg/day) or diethylstilbestrol (DES; 0.05 μg/kg/day) daily from gestation day 11 until birth. F1 females were used to generate the F2 generation, and F2 females were used to generate the F3 generation. Breeding studies at the ages of 3, 6, and 9 months were conducted to evaluate reproductive capacity over time. Further, studiesmore » were conducted to evaluate pubertal onset, litter size, and percentage of dead pups; and to calculate pregnancy rate, and mating, fertility, and gestational indices. The results indicate that BPA exposure (0.5 and 50 μg/kg/day) significantly delayed the age at vaginal opening in the F3 generation compared to vehicle control. Both DES (0.05 μg/kg/day) and BPA (50 μg/kg/day) significantly delayed the age at first estrus in the F3 generation compared to vehicle control. BPA exposure reduced gestational index in the F1 and F2 generations compared to control. Further, BPA exposure (0.5 μg/kg/day) compromised the fertility index in the F3 generation compared to control. Finally, in utero BPA exposure reduced the ability of female mice to maintain pregnancies as they aged. Collectively, these data suggest that BPA exposure affects reproductive function in female mice and that some effects may be transgenerational in nature. - Highlights: • In utero BPA delayed vaginal opening in the F3 generation compared to control. • In utero BPA delayed estrus in the F3 generation compared to control. • In utero BPA reduced the ability of F1 and F2 female mice to maintain pregnancies. • In utero BPA compromised the ability of F3 female mice to become pregnant. • Some effects of in utero BPA may be transgenerational in nature.« less
  • Mice received inhalation exposures of /sup 3/H-labeled ethylene oxide (EtO) gas at levels from 0.65 to 3.2 parts per million-hours (ppm-hr), which are below the exposure limits currently allowed for humans. Subsequently, spermatozoa were recovered from the reproductive tracts of the animals over a two-week period and assayed for the amount of bound EtO. A strong increase in the level of EtO binding occurred in late spermatid stages; these stages are also genetically sensitive to the action of EtO. Alkylation of the DNA within the sperm accounted for a very small fraction of the total sperm head alkylation, averaging aboutmore » 20 DNA alkylations per sperm per ppm-hr of exposure over the two-week period. However, alkylation of protamine, a protein unique to sperm cells, was found to be correlated with total sperm head alkylation and accounted for nearly all of the EtO binding. Protamine alkylation appears to be a significant cause of EtO-induced genetic damage in spermiogenic cells of the mammal.« less
  • Bisphenol A (BPA) is one of the most prevalent chemicals in daily-use materials, therefore, human exposure to BPA is ubiquitous. We found that low concentrations of BPA stimulate the spermatogonial GC-1 cells proliferation by G protein-coupled receptor 30 (GPR30)-mediated epidermal growth factor receptor (EGFR)-extracellular regulated kinase (ERK)-c-Fos pathway. However, through the same pathway GPR30 expression has been shown to be induced by EGF, an EGFR ligand. Thus, we want to know if low concentrations of BPA are able to induce the GPR30 expression and the possible mechanism(s) in GC-1 cells. By transient transfection with expression plasmids, 10{sup −9} M BPAmore » significantly transactivates the Gpr30-5′-flanking region through activating the GPR30, cGMP-dependent protein kinase (PKG), estrogen receptor-α (ER-α), and EFGR-ERK pathways. Furthermore, an activator protein-1 (AP-1) site located within this region is found to be responsible for the transactivation of BPA. Expectedly, through the same pathways, BPA significantly induces the gene and protein expression of GPR30. c-Fos is further observed to be strongly recruited to the AP-1 site in a chromatin immunoprecipitation assay and its dysfunction on the AP-1 site markedly suppresses the expression of GPR30, p-ERK1/2, p-Ser118-ER-α and cell proliferation by BPA. Our results demonstrate that a low-concentration BPA induces GPR30 expression through the GPR30-EFGR-ERK-c-Fos, ER-α, and PKG pathways, presumably boosting the cells proliferation via a regulatory loop. The present study provides a novel insight into the potential role of GPR30 in the initiation and progression of male germ cell cancer induced by environmentally relevant BPA. - Highlights: ► Low concentrations of BPA activate the PKG and GPR30-EFGR-ERK-ER-α pathways. ► Low concentrations of BPA activate the AP-1 site of Gpr30-5′-flanking region. ► Low concentrations of BPA induce the expression of GPR30 gene and protein. ► Low concentrations of BPA boost GC-1 cells proliferation via a regulatory loop.« less
  • Offspring of mice treated with cyclophosphamide (Cy; 1, 2.5 or 5 mg/kg) during pregnancy (6-18 days of gestation) and tested for immunocompetence from 5 to 10 weeks of age were found to have defective reticuloendothelial clearance. The main effects were: (a) increased elimination half time (T 1/2) of {sup 51}Cr-labeled SRBC from circulation, (b) decreased liver uptake of {sup 51}Cr and (c) impaired ability of the spleen, mostly affecting the female pups, to compensate for decreased liver uptake. The highest dose group suffered the most pronounced effects. This group was also found to have increased IgG immunoglobulin levels at 7more » weeks of age. IgG antibody production in response to specific antigenic stimulation and delayed hypersensitivity reactions to oxazolone did not appear to be affected by Cy treatment.« less
  • Gravid female mice received either a single subcutaneous dose of cerium citrate (80 mg Ce/kg) or an equivalent (in citrate) dose of sodium citrate on day 7 or 12 of gestation or on day 2 postpartum. To separate effects of prenatal and postnatal exposure, a cross-fostering design was employed. The weight and gross activity of the neonates were assessed on day 8 or 13 postpartum. Open-field behavioral parameters, accelerating rotarod performance, and passive avoidance learning were assessed on day 60-65 postpartum. Maternal offspring retrival latency was measured on day 3 postpartum. Maternal offspring retrieval latency was measured on day 3more » postpartum. Analyses revealed that neonatal weight was reduced both in offspring exposed to Ce in utero and in the offspring of mothers receiving Ce during lactation/suckling. Ce also appeared to affect maternal/offspring interaction: pups exposed prenatally to Ce were retrieved in less time than control pups. Except for an increased frequency of rearings in the open field of adult offspring exposed to Ce in utero, Ce exposure had no apparent effect on behavioral parameters, either in neonatal or adult offspring.« less