Multigenerational genetic effects of paternal cadmium exposure on ovarian granulosa cell apoptosis

Yi Sun; Wenchang Zhang; Yuchen Li; Jianlin Zhu; Chenchen Liu; Lingfeng Luo; Jin Liu; Chenyun Zhang

doi:10.1016/j.ecoenv.2023.115123

Multigenerational genetic effects of paternal cadmium exposure on ovarian granulosa cell apoptosis

Ecotoxicol Environ Saf. 2023 Jun 12:262:115123. doi: 10.1016/j.ecoenv.2023.115123. Online ahead of print.

Authors

Yi Sun¹, Wenchang Zhang², Yuchen Li³, Jianlin Zhu³, Chenchen Liu³, Lingfeng Luo³, Jin Liu³, Chenyun Zhang⁴

Affiliations

¹ Department of Preventive Medicine, Fujian Provincial Key Laboratory of Environmental Factors and Cancer, Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou 350122, Fujian Province, China; Key Laboratory of Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
² Department of Preventive Medicine, Fujian Provincial Key Laboratory of Environmental Factors and Cancer, Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou 350122, Fujian Province, China. Electronic address: wenchang2008@126.com.
³ Department of Preventive Medicine, Fujian Provincial Key Laboratory of Environmental Factors and Cancer, Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou 350122, Fujian Province, China.
⁴ School of Health Management, Fujian Medical University, Fuzhou 350122, Fujian Province, China. Electronic address: cyzhang@fjmu.edu.cn.

PMID: 37315360
DOI: 10.1016/j.ecoenv.2023.115123

Abstract

To explore whether paternal cadmium (Cd) exposure causes ovarian granulosa cell (GC) apoptosis in offspring and the multigenerational genetic effects. From postnatal day 28 (PND28) until adulthood (PND56), SPF male Sprague-Dawley (SD) rats were gavaged daily with varying concentrations of CdCl_2. (0, 0.5, 2, and 8 mg/kg). After treatment, the F1 generation was produced by mating with untreated female rats, and the F1 generation male rats were mated with untreated female rats to produce the F2 generation. Apoptotic bodies (electron microscopy) and significantly higher apoptotic rates (flow cytometry) were observed in both F1 and F2 ovarian GCs following paternal Cd exposure. Moreover, the mRNA (qRTPCR) or protein (Western blotting) levels of bax, bcl2, bcl-xl, caspase 3, caspase 8, and caspase 9 were changed to varying degrees. Apoptosis-related miRNAs (qRTPCR) and methylation modifications of apoptosis-related genes (bisulfite-sequencing PCR) in ovarian GCs were further detected. Compared with those of controls, the expression patterns of miRNAs in F1 and F2 offspring were different after paternal Cd exposure, while the average methylation level of apoptosis-related genes did not change significantly (except for individual loci). In summary, there are paternal genetic intergenerational and transgenerational effects on ovarian GC apoptosis induced by paternal Cd exposure. These genetic effects were related to the upregulation of BAX, BCL-XL, Cle-CASPASE 3, and Cle-CASPASE 9 in F1 and the upregulation of Cle-CASPASE 3 in F2 progeny. Important changes in apoptosis-related miRNAs were also observed.

Keywords: Apoptosis; Cadmium; Granulosa cells; Intergenerational and transgenerational effects; Paternal exposure.