Department of Animal Science & Technology, BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea.
Hum Reprod. 2020 Aug 1;35(8):1740-1752. doi: 10.1093/humrep/deaa139.
How does paternal exposure to bisphenol A (BPA) affect the fertility of male offspring in mice in future generations?
Paternal exposure to BPA adversely affects spermatogenesis, several important sperm functions and DNA methylation patterns in spermatozoa, which have both multigenerational (in F0 and F1) and partial transgenerational (mainly noticed in F2, but F3) impacts on the fertility of the offspring.
BPA, a synthetic endocrine disruptor, is used extensively to manufacture polycarbonate plastics and epoxy resins. Growing evidence suggests that exposure to BPA during the developmental stages results in atypical reproductive phenotypes that could persist for generations to come.
STUDY DESIGN, SIZE, DURATION: CD-1 male mice (F0) were treated with BPA (5 or 50 mg/kg body weight per day (bw/day)) or ethinylestradiol (EE) (0.4 μg/kg bw/day) for 6 weeks. Control mice were treated with vehicle (corn oil) only. The treated male mice were bred with untreated female mice to produce first filial generation (F1 offspring). The F2 and F3 offspring were produced similarly, without further exposure to BPA.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Histological changes in the testis along with functional, biochemical and epigenetic (DNA methylation) properties of spermatozoa were investigated. Subsequently, each parameter of the F0-F3 generations was compared between BPA-treated mice and control mice.
Paternal BPA exposure disrupted spermatogenesis by decreasing the size and number of testicular seminiferous epithelial cells, which eventually led to a decline in the total sperm count of F0-F2 offspring (P < 0.05). We further showed that a high BPA dose decreased sperm motility in F0-F2 males by mediating the overproduction of reactive oxygen species (F0-F1) and decreasing intracellular ATP (F0-F2) in spermatozoa (P < 0.05). These changes in spermatozoa were associated with altered global DNA methylation patterns in the spermatozoa of F0-F3 males (P < 0.05). Furthermore, we noticed that BPA compromised sperm fertility in mice from the F0-F2 (in the both dose groups) and F3 generations (in the high-dose group only). The overall reproductive toxicity of BPA was equivalent to or higher (high dose) than that of the tested dose of EE.
N/A.
LIMITATIONS, REASONS FOR CAUTION: Further research is required to determine the variables (e.g. lowest BPA dose) that are capable of producing changes in sperm function and fertility in future generations.
These results may shed light on how occupational exposure to BPA can affect offspring fertility in humans.
STUDY FUNDING/COMPETING INTEREST(S): This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant No. NRF-2018R1A6A1A03025159). M.S.R. was supported by Korea Research Fellowship Program through the NRF funded by the Ministry of Science and ICT (Grant No. 2017H1D3A1A02013844). There are no competing interests.
父亲暴露于双酚 A（BPA）如何影响雄性后代在未来几代中的生育能力？
父亲暴露于 BPA 会对精子发生、精子的几种重要功能和 DNA 甲基化模式产生不利影响，这些影响在多代（F0 和 F1）和部分跨代（主要在 F2 中注意到，但 F3）对后代的生育能力产生影响。
BPA 是一种合成的内分泌干扰物，广泛用于制造聚碳酸酯塑料和环氧树脂。越来越多的证据表明，在发育阶段暴露于 BPA 会导致非典型的生殖表型，这些表型可能会持续几代人。
研究设计、大小、持续时间：用 BPA（每天 5 或 50 毫克/公斤体重（bw/day））或雌二醇（EE）（0.4 微克/公斤 bw/day）处理 CD-1 雄性小鼠（F0）6 周。对照小鼠仅用载体（玉米油）处理。经处理的雄性小鼠与未经处理的雌性小鼠交配，产生第一代（F1 后代）。同样产生 F2 和 F3 后代，不再接触 BPA。
参与者/材料、设置、方法：研究了睾丸的组织学变化以及精子的功能、生化和表观遗传（DNA 甲基化）特性。随后，在 BPA 处理的小鼠和对照小鼠之间比较了 F0-F3 代的每个参数。
父亲 BPA 暴露通过减少睾丸生精上皮细胞的大小和数量来破坏精子发生，最终导致 F0-F2 后代的总精子数下降（P<0.05）。我们进一步表明，高剂量 BPA 通过介导活性氧（ROS）的过度产生（F0-F1）和降低精子内的细胞内 ATP（F0-F2）来降低 F0-F2 雄性的精子运动能力（P<0.05）。F0-F3 雄性精子中的这些变化与精子中整体 DNA 甲基化模式的改变有关（P<0.05）。此外，我们注意到 BPA 损害了 F0-F2（在两个剂量组中）和 F3 代（仅在高剂量组中）的小鼠的精子生育能力。BPA 的整体生殖毒性与测试剂量的 EE 相当或更高（高剂量）。
无。
局限性、谨慎的原因：需要进一步研究确定能够在未来几代中产生精子功能和生育能力变化的变量（例如最低 BPA 剂量）。
这些结果可能有助于阐明职业接触 BPA 如何影响人类后代的生育能力。
研究基金/竞争利益：本研究由韩国国家研究基金会（NRF）通过教育部资助的基础科学研究计划（NRF-2018R1A6A1A03025159）提供支持。M.S.R. 得到了韩国研究基金会通过科学和信息通信技术部资助的韩国研究奖学金计划（NRF 2017H1D3A1A02013844）的支持。没有竞争利益。
