Prenatal exposure to benzo[a]pyrene depletes ovarian reserve and masculinizes embryonic ovarian germ cell transcriptome transgenerationally
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE213947 | GEO | 2023/06/07
REPOSITORIES: GEO
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Project description:People are exposed to polycyclic aromatic hydrocarbons, like benzo[a]pyrene (BaP), via inhalation of particulate matter air pollution and ingestion of grilled and smoked foods. Prenatal exposure to BaP destroys germ cells in ovaries, causing earlier onset of ovarian senescence post-natally. Developing testes are affected at higher doses than ovaries. However, it is not known if adverse effects are transmitted to subsequent generations. We orally dosed pregnant female mice (F0) with 0.033, 0.2, or 2 mg/kg-day BaP or vehicle from embryonic day (E) 6.5-11.5 (F1 offspring) or E6.5-15.5 (F2 and F3). Ovarian germ cell and follicle numbers were significantly decreased in F3 females at all doses of BaP; testicular germ cells were not affected. E13.5 germ cell RNA-sequencing revealed significantly increased expression of male-specific genes in female germ cells across generations and BaP doses. Our study demonstrated that F0 BaP exposure partially disrupted sexual identity of female germ cells transgenerationally.
2023-06-07 | GSE213945 | GEO
Project description:People are exposed to polycyclic aromatic hydrocarbons, like benzo[a]pyrene (BaP), via inhalation of particulate matter air pollution and ingestion of grilled and smoked foods. Prenatal exposure to BaP destroys germ cells in ovaries, causing earlier onset of ovarian senescence post-natally. Developing testes are affected at higher doses than ovaries. However, it is not known if adverse effects are transmitted to subsequent generations. We orally dosed pregnant female mice (F0) with 0.033, 0.2, or 2 mg/kg-day BaP or vehicle from embryonic day (E) 6.5-11.5 (F1 offspring) or E6.5-15.5 (F2 and F3). Ovarian germ cell and follicle numbers were significantly decreased in F3 females at all doses of BaP; testicular germ cells were not affected. E13.5 germ cell RNA-sequencing revealed significantly increased expression of male-specific genes in female germ cells across generations and BaP doses. Our study demonstrated that F0 BaP exposure partially disrupted sexual identity of female germ cells transgenerationally.
2023-06-07 | GSE213946 | GEO
Project description:People are exposed to polycyclic aromatic hydrocarbons, like benzo[a]pyrene (BaP), via inhalation of particulate matter air pollution and ingestion of grilled and smoked foods. Prenatal exposure to BaP destroys germ cells in ovaries, causing earlier onset of ovarian senescence post-natally. Developing testes are affected at higher doses than ovaries. However, it is not known if adverse effects are transmitted to subsequent generations. We orally dosed pregnant female mice (F0) with 0.033, 0.2, or 2 mg/kg-day BaP or vehicle from embryonic day (E) 6.5-11.5 (F1 offspring) or E6.5-15.5 (F2 and F3). Ovarian germ cell and follicle numbers were significantly decreased in F3 females at all doses of BaP; testicular germ cells were not affected. E13.5 germ cell RNA-sequencing revealed significantly increased expression of male-specific genes in female germ cells across generations and BaP doses. Our study demonstrated that F0 BaP exposure partially disrupted sexual identity of female germ cells transgenerationally.
2023-06-07 | GSE213812 | GEO
Project description:People are exposed to polycyclic aromatic hydrocarbons, like benzo[a]pyrene (BaP), via inhalation of particulate matter air pollution and ingestion of grilled and smoked foods. Prenatal exposure to BaP destroys germ cells in ovaries, causing earlier onset of ovarian senescence post-natally. Developing testes are affected at higher doses than ovaries. However, it is not known if adverse effects are transmitted to subsequent generations. We orally dosed pregnant female mice (F0) with 0.033, 0.2, or 2 mg/kg-day BaP or vehicle from embryonic day (E) 6.5-11.5 (F1 offspring) or E6.5-15.5 (F2 and F3). Ovarian germ cell and follicle numbers were significantly decreased in F3 females at all doses of BaP; testicular germ cells were not affected. E13.5 germ cell RNA-sequencing revealed significantly increased expression of male-specific genes in female germ cells across generations and BaP doses. Our study demonstrated that F0 BaP exposure partially disrupted sexual identity of female germ cells transgenerationally.
2023-06-07 | GSE230356 | GEO
Project description:Polycyclic aromatic hydrocarbons like benzo[a]pyrene (BaP) are ubiquitous environmental contaminants formed during incomplete combustion of organic materials. Our prior work showed that transplacental exposure to BaP depletes ovarian follicles and increases prevalence of epithelial ovarian tumors later in life. We used the MutaMouse transgenic rodent model to address the hypothesis that ovarian mutations play a role in tumorigenesis caused by prenatal exposure to BaP. Pregnant MutaMouse females were treated with 0, 10, 20, or 40 mg/(kg day) BaP orally on gestational days 7-16, covering critical windows of ovarian development. Female offspring were euthanized at 10 weeks of age; some ovaries with oviducts were processed for follicle counting; other ovaries/oviducts and bone marrow were processed for determination of lacZ mutant frequency (MF). Mutant plaques were pooled within dose groups and sequenced to determine the mutation spectrum. BaP exposure caused highly significant dose-related decreases in ovarian follicles and increases in ovarian/oviductal and bone marrow mutant frequencies at all doses. Absence of follicles, cell packets, and epithelial tubular structures were observed with 20 and 40 mg/(kg day) BaP. Depletion of ovarian germ cells was inversely associated with ovarian MF. BaP induced primarily G > T and G > C transversions and deletions in ovaries/oviducts and bone marrow cells and produced a mutation signature highly consistent with that of tobacco smoking in human cancers. Overall, our results show that prenatal BaP exposure significantly depletes ovarian germ cells, causes histopathological abnormalities, and increases the burden of ovarian/oviductal mutations, which may be involved in pathogenesis of epithelial ovarian tumors. Environ. Mol. Mutagen. 60:410-420, 2019. © 2018 Her Majesty the Queen in Right of Canada.
| S-EPMC6615722 | biostudies-literature
Project description:Dacarbazine is commonly administered for the treatment of cancers prevalent in reproductive age females. However, investigations of off-target effects of dacarbazine on the ovary are limited. We assessed the impact of dacarbazine on the ovarian reserve of primordial follicles, essential for fertility. Eight week and 6 month old C57BL/6?J mice were administered with dacarbazine or saline on day (d)0 and d7, then sacrificed after 12?hours (h), or 14d (n?=?4-5/group). Follicle numbers, follicle density, serum AMH and corpora lutea were quantified and estrous cyclicity monitored. In reproductively young mice, dacarbazine did not affect primordial follicle numbers at 12?h, but resulted in a 36% reduction at 14d (p?<?0.05). Dacarbazine-mediated primordial follicle depletion was accelerated with age, with a 24% (p?<?0.05) and 36% (p?<?0.01) reduction at 12?h and 14d. Follicle density remained unchanged between treatment groups at either age. Dacarbazine depleted antral follicles at 14d (p?<?0.05), at both ages. Despite partial reduction of antral follicles, serum AMH, estrous cyclicity and corpora lutea (indicative of ovulation) remained unchanged between treatment groups, at both ages. Importantly, diminished ovarian reserve can result in premature ovarian insufficiency and infertility, thus, fertility preservation options should be considered for young female patients prior to dacarbazine treatment.
| S-EPMC5917018 | biostudies-literature
Project description:Benzo[a]pyrene induction of glutathione S-transferases, an activity-based protein profiling investigation
2020-05-26 | PXD010610 | Pride
Project description:BACKGROUND: Small molecule ligands often have multiple effects on the transcriptional program of a cell: they trigger a receptor specific response and additional, indirect responses ("side effects"). Distinguishing those responses is important for understanding side effects of drugs and for elucidating molecular mechanisms of toxic chemicals. RESULTS: We explored this problem by exposing cells to the environmental contaminant benzo-[a]-pyrene (B[a]P). B[a]P exposure activates the aryl hydrocarbon receptor (Ahr) and causes toxic stress resulting in transcriptional changes that are not regulated through Ahr. We sought to distinguish these two types of responses based on a time course of expression changes measured after B[a]P exposure. Using Random Forest machine learning we classified 81 primary Ahr responders and 1,308 genes regulated as side effects. Subsequent weighted clustering gave further insight into the connection between expression pattern, mode of regulation, and biological function. Finally, the accuracy of the predictions was supported through extensive experimental validation. CONCLUSION: Using a combination of machine learning followed by extensive experimental validation, we have further expanded the known catalog of genes regulated by the environmentally sensitive transcription factor Ahr. More broadly, this study presents a strategy for distinguishing receptor-dependent responses and side effects based on expression time courses.
| S-EPMC3215681 | biostudies-literature
Project description:Benzo[a]pyrene (BaP) is an environmentally relevant carcinogenic and endocrine disrupting compound that causes immediate, long-term, and multigenerational health deficits in mammals and fish. Previously, we found that BaP alters DNA methylation patterns in developing zebrafish, which may affect gene expression. Herein, we performed a genome-wide transcriptional analysis and discovered differential gene expression and splicing in developing zebrafish. Adult zebrafish were exposed to control or 42.0?±?1.9?µg/l BaP for 7 days. Eggs were collected and raised in control conditions or continuously exposed to BaP until 3.3 and 96?h post-fertilization (hpf). RNA sequencing (RNA-Seq) was conducted on zebrafish embryos and larvae. Data were analyzed to identify differentially expressed (DE) genes (changed at the gene or transcript variant level) and genes with differential exon usage (DEU; changed at the exon level). At 3.3?hpf, BaP exposure resulted in 8 DE genes and 51 DEU genes. At 96?hpf, BaP exposure altered expression in 1153 DE genes and 159 DEU genes. Functional ontology analysis by Ingenuity Pathway Analysis revealed that many disease pathways, including organismal death, growth failure, abnormal morphology of embryonic tissue, congenital heart disease, and adverse neuritogenesis, were significantly enriched for the DE and DEU genes, providing novel insights on the mechanisms of action of BaP-induced developmental toxicities. Collectively, we discovered substantial transcriptomic changes at the gene, transcript variant, and exon levels in developing zebrafish after early life BaP waterborne exposure, and these changes may lead to long-term adverse physiological consequences.
| S-EPMC4607752 | biostudies-literature
Project description:The higher molecular weight polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BaP) are typically associated with genotoxicity, however, newer evidence suggests that these compounds may also act as endocrine system disruptors. We hypothesized that altered expression of the P450 enzyme aromatase genes could be a target for reproductive or developmental dysfunction caused by BaP exposure. Aromatase is at least partially responsible for estrogen homeostasis by converting androgens into estrogens. In fish, there are two isoforms of aromatase, a predominantly ovarian form, CYP19A1, and a brain form, CYP19A2. CYP19 mRNA expression was measured following BaP exposure (0, 10, 100 microg/L waterborne for 10 or 15 days) in Fundulus adults, juveniles and embryos by in situ hybridization. The CYP19A1 expression was significantly decreased after BaP exposure in the 3-month-old Fundulus immature oocytes, but BaP did not affect CYP19A1 expression at any stage in adult oocytes. In embryo brains, BaP significantly decreased CYP19A2 compared to controls by 3.6-fold at 14 days post-fertilization. In adults, CYP19A2 expression was decreased significantly in the pituitary and hypothalamus (81% and 85% of controls, respectively). Promoter regions of Fundulus CYP19s were cloned, and putative response elements in the CYP19A1 and CYP19A2 promoters such as CRE, AhR and ERE may be involved in BaP-mediated changes in CYP19 expression. In order to compare the mechanism of BaP-mediated inhibition with that of a known aromatase inhibitor, fish were also exposed to fadrozole (20 and 100 microg/L). Fadrozole did not significantly decrease the mRNA expression in embryos or adult Fundulus. However, aromatase enzyme activity was significantly decreased in adult ovary and brain tissues. These studies provide a greater molecular understanding of the mechanisms of action of BaP and its potential to impact reproduction or development.
| S-EPMC2530897 | biostudies-literature