Small Noncoding RNAs Contribute to Sperm Oxidative Stress-Induced Programming of Behavioral and Metabolic Phenotypes in Offspring

Abstract

There is growing evidence that paternal environmental information alters small noncoding RNAs (sncRNAs) in sperm and in turn can induce alterations of metabolic and behavioral phenotypes of the next generation. However, the potential mediators of the effects remain to be elucidated. A great diversity of environmental insults and stresses can convergently induce the elevation of reactive oxygen species (ROS) in sperm; nonetheless, it remains unclear whether ROS mediates the biogenesis of sncRNAs in sperm and participates in the reprogramming of offspring phenotypes. Here, we show that ROS could induce the alteration of sncRNA profiles in sperm, especially for transfer RNA-derived small RNAs (tsRNAs) and ribosomal RNA-derived small RNAs (rsRNAs). Zygotic injection of 29-34 nt RNA fractions (predominantly tsRNAs and rsRNAs) from oxidative stress (OS) sperm could induce depressive-like and anxiety-like behaviors in male offspring. Moreover, zygotic injection with synthetic RNAs partially resembled OS sperm-induced depressive-like and anxiety-like behaviors in offspring. Male offspring maintained on a chow diet was found to develop impaired glucose tolerance and hyperactive hepatic gluconeogenesis, accompanied by the upregulation of hepatic gluconeogenic and lipolytic genes. Together, our results have shown that ROS-induced alteration of sncRNA profiles in sperm contributes to the alterations of behavioral and metabolic phenotypes of the offspring.

DNA damage in testicular germ cells and spermatozoa. When and how is it induced? How should we measure it? What does it mean?

“…In the human, these sperm-borne epigenetic factors include an intact centriole that will orchestrate cell division in the progeny, a critical enzyme (phospholipase C, zeta) that will initiate calcium oscillations in the ooplasm in order to trigger the developmental process, as well as a range of small non-coding RNA species that will ultimately impact the metabolic and behavioural phenotype of the offspring. [1][2][3] Paternally-mediated disruptions to embryonic development occur when the integrity of the paternal genome is compromised [4][5][6] or when the spermatozoon's repertoire of developmental epigenetic regulators is damaged. 7,8 The evident importance of paternally mediated genetic/epigenetic changes to the long-term health trajectory of the offspring, raises important questions about how such damage arises, how it can be detected and the relative significance of such factors in the etiology of human disease.…”

“…The successful initiation of embryogenesis depends, in turn, on the ability of the spermatozoon to deliver to the egg both an appropriately programmed paternal genome and a range of epigenetic factors that will shape the developmental process in response to a variety of metabolic and environmental factors. In the human, these sperm‐borne epigenetic factors include an intact centriole that will orchestrate cell division in the progeny, a critical enzyme (phospholipase C, zeta) that will initiate calcium oscillations in the ooplasm in order to trigger the developmental process, as well as a range of small non‐coding RNA species that will ultimately impact the metabolic and behavioural phenotype of the offspring 1–3 …”