In Utero and Lactational Exposure to Flame Retardants Disrupts Rat Ovarian Follicular Development and Advances Puberty

Abstract Brominated flame retardants (BFRs), including polybrominated diphenyl ethers and hexabromocyclododecane, leach out from consumer products into the environment. Exposure to BFRs has been associated with effects on endocrine homeostasis. To test the hypothesis that in utero and lactational exposure to BFRs may affect the reproductive system of female offspring, adult female Sprague Dawley rats were fed diets formulated to deliver nominal doses (0, 0.06, 20, or 60 mg/kg/day) of a BFR dietary mixture mimicking the relative congener levels in house dust from prior to mating until weaning. Vaginal opening and the day of first estrus occurred at a significantly earlier age among offspring from the 20 mg/kg/day BFR group, indicating that the onset of puberty was advanced. Histological analysis of ovaries from postnatal day 46 offspring revealed an increase in the incidence of abnormal follicles. A toxicogenomic analysis of ovarian gene expression identified upstream regulators, including HIF1A, CREB1, EGF, the β-estradiol, and PPARA pathways, predicted to be downregulated in the 20 or 60 mg/kg/day group and to contribute to the gene expression patterns observed. Thus, perinatal exposure to BFRs dysregulated ovarian folliculogenesis and signaling pathways that are fundamental for ovarian function in the adult.

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The brominated flame retardants TBECH and DPTE alter prostate growth, histology and gene expression patterns in the mouse

Reproductive Toxicology ◽

10.1016/j.reprotox.2021.04.002 ◽

2021 ◽

Vol 102 ◽

pp. 43-55

Author(s):

Ceyhun Bereketoglu ◽

Carina Modig ◽

Ajay Pradhan ◽

Patrik L. Andersson ◽

Sotiria Stasinopoulou ◽

...

Keyword(s):

Gene Expression ◽

Flame Retardants ◽

Expression Patterns ◽

Brominated Flame Retardants ◽

Gene Expression Patterns ◽

Prostate Growth

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Large-Scale Metadata Analysis of Ovary Based Multi-Omics Datasets for Understanding the Genes Regulating Litter Size

10.21203/rs.3.rs-22487/v1 ◽

2020 ◽

Author(s):

Ayyappa Kumar Sista Kameshwar ◽

Julang Li

Keyword(s):

Gene Expression ◽

Differentially Expressed Genes ◽

Litter Size ◽

Large Scale ◽

Expression Patterns ◽

Genetic Selection ◽

Follicular Development ◽

Oocyte Quality ◽

Differentially Expressed ◽

Metadata Analysis

Abstract Background : Litter size is a very important production index in the livestock industry, which is controlled by various complex physiological processes. To understand and reveal the common gene expression patterns involved in controlling prolificacy, we have performed a large-scale metadata analysis of five genome-wide transcriptome datasets of pig and sheep ovary samples obtained from high and low litter groups, respectively. We analyzed separately each transcriptome dataset using GeneSpring v14.8 software by implementing standard, generic analysis pipelines and further compared the list of most significant and differentially expressed genes obtained from each dataset to identify genes that are found to be common and significant across all the studies. Results : We have observed a total of 62 differentially expressed genes common among more than two gene expression datasets. The KEGG pathway analysis of most significant genes has shown that they are involved in metabolism, the biosynthesis of lipids, cholesterol and steroid hormones, immune system, cell growth and death, cancer-related pathways and signal transduction pathways. Of these 62 genes, we further narrowed the list to the 25 most significant genes by focusing on the ones with fold change >1.5 and p<0.05. These genes are CYP11A1, HSD17B2, STAR, SCARB1, IGSF8, MSMB, SERPINA1 , FAM46C, HEXA, PTTG1, TIMP1, FAM167B, CCNG1, FAXDC2, HMGCS1, L2HGDH, Lipin1, MME, MSMO1, PARM1, PTGFR, SLC22A4, SLC35F5, CCNA2, CENPU, CEP55, RASSF2, and SLC16A3 . Conclusions : Interestingly, comparing the list of genes with the list of genes obtained from our literature search analysis, we found only three genes in common. These genes are HEXA, PTTG1, and TIMP1. Our finding points to the potential of a few genes that may be important for ovarian follicular development and oocyte quality. Future studies revealing the function of these genes will further our understanding of how litter size is controlled in the ovary while also providing insight on genetic selection of high litter gilts.

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Maternal and Post-weaning High-Fat Diets Produce Distinct DNA Methylation Patterns in Hepatic Metabolic Pathways within Specific Genomic Contexts

International Journal of Molecular Sciences ◽

10.3390/ijms20133229 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3229 ◽

Cited By ~ 4

Author(s):

Moody ◽

Wang ◽

Jung ◽

Chen ◽

Pan

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Metabolic Pathways ◽

Expression Patterns ◽

Sprague Dawley ◽

High Fat ◽

Differentially Methylated Genes ◽

High Fat Diets ◽

Diet Intake ◽

Fat Diets

Calorie-dense high-fat diets (HF) are associated with detrimental health outcomes, including obesity, cardiovascular disease, and diabetes. Both pre- and post-natal HF diets have been hypothesized to negatively impact long-term metabolic health via epigenetic mechanisms. To understand how the timing of HF diet intake impacts DNA methylation and metabolism, male Sprague–Dawley rats were exposed to either maternal HF (MHF) or post-weaning HF diet (PHF). At post-natal week 12, PHF rats had similar body weights but greater hepatic lipid accumulation compared to the MHF rats. Genome-wide DNA methylation was evaluated, and analysis revealed 1744 differentially methylation regions (DMRs) between the groups with the majority of the DMR located outside of gene-coding regions. Within differentially methylated genes (DMGs), intragenic DNA methylation closer to the transcription start site was associated with lower gene expression, whereas DNA methylation further downstream was positively correlated with gene expression. The insulin and phosphatidylinositol (PI) signaling pathways were enriched with 25 DMRs that were associated with 20 DMGs, including PI3 kinase (Pi3k), pyruvate kinase (Pklr), and phosphodiesterase 3 (Pde3). Together, these results suggest that the timing of HF diet intake determines DNA methylation and gene expression patterns in hepatic metabolic pathways that target specific genomic contexts.

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In Utero and Lactational Exposure of Sprague-Dawley Rats to Diadzein Disrupts Ovarian Follicle Maturation.

Biology of Reproduction ◽

10.1093/biolreprod/83.s1.616 ◽

2010 ◽

Vol 83 (Suppl_1) ◽

pp. 616-616

Author(s):

Monika G. Baldridge ◽

Stanislaw K. Miaskowski

Keyword(s):

Ovarian Follicle ◽

In Utero ◽

Sprague Dawley ◽

Lactational Exposure ◽

Sprague Dawley Rats ◽

Follicle Maturation

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Behavioral and thyroid effects of in utero and lactational exposure of Sprague–Dawley rats to the polybrominated diphenyl ether mixture DE71

Neurotoxicology and Teratology ◽

10.1016/j.ntt.2015.08.002 ◽

2015 ◽

Vol 52 ◽

pp. 127-142 ◽

Cited By ~ 16

Author(s):

W.J. Bowers ◽

P.M. Wall ◽

J.S. Nakai ◽

A. Yagminas ◽

M. Wade ◽

...

Keyword(s):

Diphenyl Ether ◽

In Utero ◽

Polybrominated Diphenyl Ether ◽

Sprague Dawley ◽

Lactational Exposure ◽

Ether Mixture ◽

Sprague Dawley Rats

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Effects of Polybrominated Diphenyl Ethers on Child Cognitive, Behavioral, and Motor Development

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph15081636 ◽

2018 ◽

Vol 15 (8) ◽

pp. 1636 ◽

Cited By ~ 17

Author(s):

Elizabeth Gibson ◽

Eva Siegel ◽

Folake Eniola ◽

Julie Herbstman ◽

Pam Factor-Litvak

Keyword(s):

Thyroid Function ◽

Motor Development ◽

Polybrominated Diphenyl Ethers ◽

Flame Retardants ◽

Diphenyl Ether ◽

Geographic Location ◽

Maternal Blood ◽

In Utero ◽

Environmental Chemicals ◽

Relevant Effect

Polybrominated Diphenyl Ether (PBDE) flame retardants are environmental chemicals that cross the placenta during pregnancy and have shown evidence of neurotoxicity. As the in utero period is a sensitive developmental window, such exposure may result in adverse childhood outcomes. Associations between in utero PBDE exposure and neurodevelopment are found in animal models and increasingly in human population studies. Here, we review the epidemiological evidence of the association between prenatal exposure to PBDEs and motor, cognitive, and behavioral development in infants and children. Published work suggests a negative association between PBDE concentrations and neurodevelopment despite varying PBDE congeners measured, bio-specimen matrix used, timing of the biological sampling, geographic location of study population, specific developmental tests used, age of children at time of testing, and statistical methodologies. This review includes 16 published studies that measured PBDE exposure in maternal blood during pregnancy or in cord blood at delivery and performed validated motor, cognitive, and/or behavioral testing at one or more time during childhood. We evaluate possible mediation through PBDE-induced perturbations in thyroid function and effect measure modification by child sex. While the majority of studies support an adverse association between PBDEs and neurodevelopment, additional research is required to understand the mechanism of action, possibly through the perturbations in thyroid function either in the pregnant woman or in the child, and the role of biologically relevant effect modifiers such as sex.

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Effects of polybrominated diphenyl ethers on thyroid hormone, neurodevelopment and fertility in rodents and humans

International Journal of Occupational Medicine and Environmental Health ◽

10.2478/s13382-013-0138-7 ◽

2013 ◽

Vol 26 (4) ◽

Cited By ~ 32

Author(s):

Marta Czerska ◽

Marek Zieliński ◽

Joanna Kamińska ◽

Danuta Ligocka

Keyword(s):

Thyroid Hormone ◽

Polybrominated Diphenyl Ethers ◽

Flame Retardants ◽

Experimental Studies ◽

Reproductive Organs ◽

Consumer Products ◽

Psychomotor Development ◽

Human Breast Milk ◽

Postnatal Exposure ◽

Diphenyl Ethers

AbstractPolybrominated diphenyl ethers (PBDEs) are used as flame retardants. Due to their widespread use in many consumer products, PBDEs can be found in food as well as in the environment. Their presence has also been found in the human serum, human adipose tissue and human breast milk. Results of experimental studies suggest that the presence of PBDE in the environment is not neutral to our health. In rats and mice exposed to PBDE disturbances in thyroid hormone homeostasis and reproductive system such as changes in reproductive organs weight and disorders in sperm motility and motion were found. In rodents, pre- and postnatal exposure to PBDE can cause neurobehavioral effects. Also in humans disturbances in thyroid hormone system, weight of reproductive organs and concentrations of sex hormones associated with PBDEs serum concentrations were found. Exposure to PBDEs during pregnancy may lead to slower mental and psychomotor development in infants. In this paper the results of previous animal and human studies are reviewed.

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Environmentally relevant mixtures of phthalates and phthalate metabolites differentially alter the cell cycle and apoptosis in mouse neonatal ovaries†

Biology of Reproduction ◽

10.1093/biolre/ioab010 ◽

2021 ◽

Author(s):

Genoa R Warner ◽

Daryl D Meling ◽

Kathy M De La Torre ◽

Karen Wang ◽

Jodi A Flaws

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Ovarian Function ◽

Consumer Products ◽

Continuous Exposure ◽

Phthalate Metabolites ◽

Proliferation And Apoptosis ◽

Cell Cycle Inhibitors ◽

Phthalate Metabolite ◽

Ethylhexyl Phthalate

Abstract Phthalates are a group of chemicals used as additives in various consumer products, medical equipment, and personal care products. Phthalates and their metabolites are consistently detected in humans, indicating widespread and continuous exposure to multiple phthalates. Thus, environmentally relevant mixtures of phthalates and phthalate metabolites were investigated to determine the effects of phthalates on the function of the ovary during the neonatal period of development. Neonatal ovaries from CD-1 mice were cultured with either dimethyl sulphoxide (DMSO; vehicle control), phthalate mixture (0.1–100 μg/mL), or phthalate metabolite mixture (0.1–100 μg/mL). The phthalate mixture was composed of 35% diethyl phthalate, 21% di(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% diisononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. The phthalate metabolite mixture was composed of 37% monoethyl phthalate, 19% mono(2-ethylhexyl) phthalate, 15% monobutyl phthalate, 10% monoisononyl phthalate, 10% monoisobutyl phthalate, and 8% monobenzyl phthalate. After 96 hours of culture, ovaries were harvested for histological analysis of folliculogenesis, gene expression analysis of cell cycle and apoptosis regulators, and immune staining for cell proliferation and apoptosis. The metabolite mixture significantly decreased the number and percentage of abnormal follicles (100 μg/mL) compared to controls. The metabolite mixture also significantly increased the expression of cell cycle inhibitors (100 μg/mL) and the anti-apoptotic factor Bcl2l10 (10 μg/mL) compared to controls. The phthalate mixture did not significantly alter gene expression or follicle counts, but ovaries exposed to the phthalate mixture (0.1 μg/mL) exhibited marginally significantly increased apoptosis as revealed by DNA fragmentation staining. Overall, these data show that parent phthalates and phthalate metabolites differentially impact ovarian function.

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