Undernutrition Affects Cell Survival, Oxidative Stress, Ca2+ Handling and Signaling Pathways in Vas Deferens, Crippling Reproductive Capacity

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Abstract

Background

The aim of this work was to investigate the mechanisms by which chronic malnutrition (CM) affects vas deferens function, leading to compromised reproductive capacity. Previous studies have shown that maternal malnutrition affects the reproductive tracts of adult male offspring. However, little is known about the effects of CM, a widespread life-long condition that persists from conception throughout growth to adult life.

Methodology/Principal Findings

Young adult male rats, which were chronically malnourished from weaning, presented decreased total and haploid cells in the vas deferens, hypertrophy of the muscle layer in the epididymal portion of the vas deferens and intense atrophy of the muscular coat in its prostatic portion. At a molecular level, the vas deferens tissue of CM rats exhibited a huge rise in lipid peroxidation and protein carbonylation, evidence of an accentuated increase in local reactive oxygen species levels. The kinetics of plasma membrane Ca ²⁺-ATPase activity and its kinase-mediated phosphorylation by PKA and PKC in the vas deferens revealed malnutrition-induced modifications in velocity, Ca ²⁺ affinity and regulation of Ca ²⁺ handling proteins. The severely crippled content of the 12-kDa FK506 binding protein, which controls passive Ca ²⁺ release from the sarco(endo) plasmic reticulum, revealed another target of malnutrition related to intracellular Ca ²⁺ handling, with a potential effect on forward propulsion of sperm cells. As a possible compensatory response, malnutrition led to enhanced sarco(endo) plasmic reticulum Ca ²⁺-ATPase activity, possibly caused by stimulatory PKA-mediated phosphorylation.

Conclusions/Significance

The functional correlates of these cellular and molecular hallmarks of chronic malnutrition on the vas deferens were an accentuated reduction in fertility and fecundity.

Related collections

Most cited references 34

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Recent advances in understanding of male infertility have implicated two major causative factors, oxidative stress and Y chromosome deletions. A major cause of oxidative stress appears to be the high rate of reactive oxygen species generation associated with the retention of excess residual cytoplasm in the sperm midpiece. Other possible causes include the redox cycling of xenobiotics, and antioxidant depletion or apoptosis. Oxidative stress induces peroxidative damage in the sperm plasma membrane and DNA damage in both the mitochondrial and nuclear genomes. Nuclear DNA damage in the germ line of the father may be associated with pathology in the offspring, including childhood cancer and infertility. Gene deletions on the non-recombining region of the Y chromosome account for the infertility observed in about 15% of patients with azoospermia and 5-10% of subjects with severe oligozoospermia. The Y chromosome is particularly susceptible to gene deletions because of the inability of the haploid genome to deploy recombination repair in retrieving lost genetic information. Aberrant recombination, defective chromatin packaging, abortive apoptosis and oxidative stress may all be involved in the aetiology of DNA damage in the germ line. The factors responsible for Y chromosome deletions in spermatozoa remain unresolved but may be one facet of a central reproductive problem: controlling the amount of oxidative stress experienced by germ cells during their differentiation and maturation in the male reproductive tract.

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Most important processes in cell life are regulated by calcium (Ca2+). A number of mechanisms have thus been developed to maintain the concentration of free Ca2+ inside cells at the level (100-200nM) necessary for the optimal operation of the targets of its regulatory function. The systems that move Ca2+ back and forth across membranes are important actors in its control. The plasma membrane calcium ATPase (PMCA pump) which ejects Ca2+ from all eukaryotic cell types will be the topic of this contribution. The pump uses a molecule of ATP to transport one molecule of Ca2+ from the cytosol to the external environment. It is a P-type ATPase encoded by four genes (ATP2B1-4), the transcripts of which undergo different types of alternative splicing. Many pump variants thus exist. Their multiplicity is best explained by the specific Ca2+ demands in different cell types. In keeping with these demands, the isoforms are differently expressed in tissues and cell types and have differential Ca2+ extruding properties. At very low Ca2+ concentrations the PMCAs are nearly inactive. They must be activated by calmodulin, by acid phospholipids, by protein kinases, and by other means, e.g., a dimerization process. Other proteins interact with the PMCAs (i.e., MAGUK and NHERF at the PDZ domain and calcineurin A in the main intracellular domain) to sort them to specific regions of the cell membrane or to regulate their function. In some cases the interaction is isoform, or even splice variant specific. PMCAs knock out (KO) mice have been generated and have contributed information on the importance of PMCAs to cells and organisms. So far, only one human genetic disease, hearing loss, has been traced back to a PMCA defect.

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Author and article information

Contributors

Daniel Tomé: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 26 July 2013

Volume: 8

Issue: 7

Electronic Location Identifier: e69682

Affiliations

[1 ]Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

[2 ]Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

[3 ]National Institute of Science and Technology for Structural Biology and Bioimaging, Rio de Janeiro, Brazil

Paris Institute of Technology for Life, Food and Environmental Sciences, France

Author notes

* E-mail: lara@ 123456icb.ufrj.br

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: HM-F CGPB AMS LCB CMT FLO RTN SSV ME-L AV LSL VMNC. Performed the experiments: HM-F CGPB AMS LCB FLO RTN. Analyzed the data: HM-F CGPB AMS LCB CMT FLO RTN SSV ME-L AV LSL VMNC. Contributed reagents/materials/analysis tools: HM-F CGPB AMS LCB CMT FLO RTN SSV ME-L AV LSL VMNC. Wrote the manuscript: HM-F AV LSL VMNC.

Article

Publisher ID: PONE-D-12-33898

DOI: 10.1371/journal.pone.0069682

PMC ID: 3724910

PubMed ID: 23922775

SO-VID: 96dc1f61-61c9-4eda-89b2-264c4bf6c17f

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 1 November 2012

Date accepted : 17 June 2013

Funding

This work has been supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação José Bonifácio/UFRJ, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Institutos Nacionais de Ciência e Tecnologia (Brazil). Humberto Muzi-Filho and Alessandro M. Souza were recipients of a fellowship from FAPERJ. Camila G. P. Bezerra was recipient of a fellowship from CNPq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.