Superfund Research Program

Development of Biomarkers for Male Reproductive Toxicity and Their Implications for Male-Mediated Developmental Toxicity

Release Date: 10/20/1999

About five out of every one hundred newborns suffer from major birth defects, many of which are thought to be caused by an interaction between one or more genes of the developing fetus and some environmental factor such as maternal exposure to certain medications, alcohol, or other chemicals during pregnancy. However, in recent years evidence has been accumulating which suggests some forms of developmental toxicity have a paternal origin. Several epidemiological studies have shown associations between paternal occupational exposures and abnormal pregnancy outcomes. Animal studies provide additional evidence for a paternal contribution to adverse developmental effects in offspring.

These findings have generated interest in an area of research known as male-mediated genotoxicity, which is concerned with understanding how paternal exposures to chemicals might cause genetic damage in the father's sperm that leads to genetic abnormalities in newborns. Investigating this relationship has been hindered though by the limited number of genetic biomarkers for human sperm.

To provide new tools for the study of male-mediated developmental effects, researchers at the Lawrence Livermore National Laboratory (LLNL) -- a partner in the University of California-Berkeley (UC-Berkeley) Superfund Basic Research Program -- have developed a set of biomarkers for the detection of chromosomal abnormalities in sperm. The current work is focused on a specific type of genetic damage known as sperm aneuploidy, which is an abnormal number of chromosomes in the sperm.

Sperm aneuploidy is an important category of chromosomal damage that is transmitted by the father. Evidence from both animal and human studies indicates these genetically defective sperm can fertilize. Thus, a tool for detecting aneuploid sperm would be useful not only for characterizing the heritable contribution of paternally-mediated effects in offspring, but also for identifying men who may be at risk for fathering an abnormal pregnancy or a child with a birth defect.

To evaluate the new sperm aneuploidy biomarkers, the LLNL researchers, in collaboration with scientists at UC-Berkeley, have been studying families that have children with Klinefelter Syndrome, which is a chromosome abnormality that occurs only in male offspring and results from an extra sex chromosome in the genetic makeup. Instead of having two sex chromosomes (XY) in each cell of the body, males with this disorder have an extra X chromosome (XXY). The extra sex chromosome sometimes comes from the father.

The researchers have successfully developed and optimized a polymerase chain reaction method for characterizing the parental origin of X chromosomes. This method has been used to determine which parent contributed the extra X chromosome in 36 families that have children with Klinefelter Syndrome. The scientists found that the extra chromosome was paternally contributed in 10 families and maternally contributed in 26 families.

In addition, the researchers applied a new fluorescence in situ hybridization assay to detect aneuploidy in human sperm. Using this assay, the scientists determined that the fathers who contributed the extra sex chromosome to their offspring had a significantly higher rate of aneuploid sperm than the fathers of maternally-inherited Klinefelter Syndrome children. Moreover, the frequencies of aneuploid sperm increased with age. These results support the hypothesis that men with an elevated frequency of aneuploid sperm may be at a higher risk of fathering a child with aneuploidy, and that elevated frequencies of aneuploidy are more likely in older men.

This information is critical for understanding the predictive value of aneuploid sperm and for identifying possible underlying factors, including environmental ones, for fathering aneuploid children. These results also provide one of the first direct examples of a connection between abnormalities in the father's sperm and the health of offspring, and may serve as a possible mechanism of developmental toxicity mediated by the father. Furthermore, the methods developed through this research may provide a means of studying the relationship between paternal environmental exposures and adverse birth outcomes, which is an emerging area of importance in environmental health.

For More Information Contact:

Andrew J Wyrobek
Lawrence Livermore National Laboratory
Health Effects Genetics Division, L-448
Biology and Biotechnology Research Program
Berkeley, California 94551
Phone: 925-422-6296

Brenda Eskenazi
University of California-Berkeley
Environmental Health Sciences
140 Warren Hall
Berkeley, California 94720-7360
Phone: 510-642-3496

To learn more about this research, please refer to the following sources:

  • Eskenazi B, Chuu Y, Kidd SA, Lowe X, Aylstock M, Weisiger K, Moore DH, Wyrobek AJ. 1998. Elevated frequencies of aneuploid sperm (x-y and 21-21) in fathers of boys with klinefelter syndrome (47, x-x-y), when the extra x-chromosome was of paternal origin. Am J Epidemiol 147(11):S11.
  • Lowe X, Eskenazi B, Kidd SA, Alme A, Weisiger K, Aylstock M, Nelson DE, Wyrobek AJ. 1998. Sperm disomy 21 is associated with sex chromosomal aneuploidies but does not preferentially segregate with the Y chromosome: a study of 38 healthy fertile men. Am J Hum Genet 63(4):A143.
  • Sloter E, Lowe X, Nath J, Wyrobek AJ. 1998. A novel multi-color FISH method for human sperm demonstrates that post-meiotic chromosome breaks occur more frequently than duplications and deletions. Am J Hum Genet 63(4):A150.
  • Sloter E, Lowe X, Nath J, Wyrobek AJ. 1998. Detection of chromosome breaks and aneuploidies in human sperm by multicolor fluorescence in situ hybridization. Environ Mol Mutagen 31(29):61.

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