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Published on: July 29, 2019
Cadmium Exposure in Male Rats Results in Ovarian Granulosa Cell Apoptosis in Female Offspring and Paternal Genetic
Qingyu Li1, Yuchen Li1, Jianlin Zhu1
1Department of Preventive Medicine, Fujian Provincial Key Laboratory of Environment Factors and Cancer, Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China.
Abstract:
The aim of this study was to investigate whether the damage to male offspring induced by cadmium (Cd) exposure during embryonic period leads to the apoptosis of ovarian granulosa cells (OGCs) in the next generation of female offspring, and whether this apoptosis in the offspring was due to paternal genetic effects. Pregnant Sprague-Dawley (SD) rats were exposed to CdCl2 (0, 0.5, 2.0, or 8.0 mg/kg) by gavage daily for 20 days to produce the filial 1 (F1) generation. F1 males were mated with newly purchased females to produce the F2 generation, and the F3 generation was generated in the same way. No apoptotic bodies were observed in the OGCs of either the F2 or F3 generation as shown by electron microscopy, and a reduced OGC apoptosis rate (detected by flow cytometry) was observed in F2 OGCs from the Cd-exposed group. Moreover, the mRNA (qRT-PCR) levels of Bax and Bcl-2 and the protein (western blotting) level of pro-caspase-8 increased in the F2 generation (p < 0.05). The expression of apoptosis-related miRNAs (qRT-PCR) and methylation of apoptosis-related genes (determined via bisulfite-sequencing PCR) in OGCs were further determined. Compared with those of the controls, the expression patterns of microRNAs (miRNAs) in the F2 offspring were different in the Cd-exposed group. The miR-92a-2-5p expression levels were decreased in both the F2 and F3 generations (p < 0.05), while the average methylation level of apoptosis-related genes did not change significantly (except for individual loci). In summary, this study showed that the paternal genetic intergenerational effect of male Cd exposure during embryonic period induced apoptosis of OGCs in the offspring was weakened, and the transgenerational effect disappeared; nevertheless, intergenerational and transgenerational changes in apoptosis-related genes, epigenetic modifications, DNA methylation, and miRNAs were observed, and may be important for understanding the homeostatic mechanisms of the body to alleviate the intergenerational transmission of Cd-induced damage.
Insights
Paternal cadmium exposure during embryonic development weakened ovarian granulosa cell apoptosis in offspring, with effects diminishing across generations. Epigenetic changes and altered microRNA levels were observed, suggesting a protective response to cadmium toxicity.
Area of Science:
- Reproductive toxicology
- Epigenetics
- Developmental biology
Background:
- Cadmium (Cd) is a toxic heavy metal with known adverse effects on reproduction.
- Intergenerational and transgenerational effects of environmental exposures are increasingly recognized.
- Ovarian granulosa cells (OGCs) are crucial for ovarian function and oocyte development.
Purpose of the Study:
- To investigate if embryonic cadmium exposure in male rats induces ovarian granulosa cell apoptosis in female offspring.
- To determine if these effects are mediated by paternal genetic effects.
- To explore the underlying epigenetic mechanisms, including microRNA and DNA methylation changes.
Main Methods:
- Exposure of pregnant Sprague-Dawley rats to cadmium chloride (CdCl2) during gestation.
- Generation of F1, F2, and F3 offspring through mating protocols.
- Assessment of OGC apoptosis using electron microscopy and flow cytometry.
- Analysis of apoptosis-related gene and microRNA expression via qRT-PCR and Western blotting.
- Evaluation of DNA methylation patterns using bisulfite-sequencing PCR.
Main Results:
- Reduced OGC apoptosis was observed in F2 offspring from cadmium-exposed groups.
- Increased mRNA levels of Bax and Bcl-2, and protein levels of pro-caspase-8 were noted in F2 OGCs.
- Distinct microRNA expression patterns, including decreased miR-92a-2-5p, were found in F2 and F3 generations.
- No significant changes in the average methylation level of apoptosis-related genes were observed, except for individual loci.
Conclusions:
- Paternal cadmium exposure during embryonic development induced a weakened intergenerational effect on OGC apoptosis, with transgenerational effects disappearing.
- Intergenerational and transgenerational alterations in apoptosis-related genes, epigenetic modifications, and microRNAs suggest a homeostatic mechanism to mitigate cadmium-induced damage.
- These findings contribute to understanding the body's adaptive responses to environmental toxicants across generations.
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