Our Stolen Futurea book by Theo Colborn, Dianne Dumanoski, and John Peterson Myers
 
 

 

  Susiarjo, M, TJ Hassold, E Freeman and PA Hunt. 2007. Bisphenol A Exposure In Utero Disrupts Early Oogenesis in the Mouse. PLoS Genetics, 3(1): e5. doi:10.1371/journal.pgen.0030005.

Experiments with pregnant mice reveal that exposure to doses of bisphenol A (BPA) within the range of common human exposures causes chromosomally abnormal grandchildren.

 

News coverage of bisphenol A

More news about
 

This effect is possible because female mammals-- including mice and humans-- form their eggs while still in their mother's womb. Thus when a 'grandmother' mouse is exposed to bisphenol A, not only are her direct progeny exposed, but also the eggs that will become her grandchildren.

The exposure to BPA during pregnancy disturbs early egg development in the unborn female fetuses. When these fetuses reach adulthood, the perturbations are translated into an increase in chromosomally-abnormal eggs and embryos.

Chromosome abnormalities are the largest known cause of spontaneous miscarriage in people.

These findings reveal a second major impact of low level BPA on chromosomes. Previous work has shown that BPA exposure during late stages of egg development cause errors in chromosome allocation, a result called aneuploidy. This new research shows that egg formation is also vulnerable at very early stages, while the eggs are being formed within a fetus.

In commentary (Scrambling Eggs in Plastic Bottles) published along with Susiarjo et al., two scientific experts in the field conclude "these observations represent the most convincing demonstration to date that environmental exposures may affect meiotic processes in mammals."

 

What did they do? Susiarjo et al. carried out a series of experiments first to characterize the impact of BPA on chromosomes of mice exposed in the womb, and then to explore the molecular mechanisms that might be responsible for the damage they observed.

They began by exposing pregnant mice to BPA by implanting pellets within them designed to release 400 nanograms of BPA daily. This is equivalent to 20 parts per billion of body weight per day and is within the range of exposure that many people experience. The EPA and FDA safety threshold-- based upon data gathered in the 1980's-- says that 50 parts per billion per day is safe.

 

Context. Except for sperm and egg, all cells in mice, people, insects, plants, etc., normally have 2 copies of each chromosome. Humans have 23 pairs of chromosomes, 46 chromosomes all told. The members of a pair are called homologous chromosomes.

To form sperm and eggs, cells undergo meiosis. Meiosis is a multi-stage process of cell division that allocates one copy of each chromosome to the sperm or egg. Then when fertilization occurs, the fertilized egg once again has two copies, one each from father and mother. During part of meiosis, homologous chromosomes are paired, lined up parallel to each other and literally intertwined. This state is called synapsis.

Errors during meiosis undermine the viability of sperm and egg. Severe errors can lead either sperm or egg to be completely inviable, or to adverse conditions following fertilization, including embryonic death, spontaneous abortion, or birth defects. For example,in people, Down Syndrome results from the failure of chromosomes to separate properly during meiosis in a way that causes the fertilized egg to have 3 copies of Chromosome 21. Getting the wrong number of chromosomes, or aneuploidy, is the largest known cause of spontaneous miscarriage in people.

More on meiosis.

They then examined the effect of exposure on chromosomes at different stages of development, including in the eggs of females exposed in the womb and in the embryos of females exposed in the womb. The embryos are the 'grandchildren' of the female mice that were exposed while pregnant.

For the experiments above, Susiarjo et al. used mice that had a full complement of estrogen receptors. In a separate set of experiments, they worked with two genetic variants of mice, one lacking working copies of the genes that produce either estrogen receptor α or estrogen receptor ß. Estrogenic compounds normally bind with these two receptor types in the process of turning on genes that are responsive to estrogens. Scientists use genetic mutants, called 'knock-outs,' that lack one or more receptor types, to examine some of the molecular mechanisms involved in causing the observed effects.

What did they find? In eggs from the ovaries of 18.5 day old fetuses (surgically removed from the adult mothers who were exposed while pregnant), Susiarjo et al. observed highly significant increases in chromosomal abnormalites.

As shown in the figure below and to the left, a lower percentage of BPA exposed eggs had normal chromosomes and various errors were much more common.

BPA-exposed eggs had higher rates of 'incomplete synapsis,' ... when homologous chromosomes don't come together (synapse) properly during meiosis (compare micrographs below and to right).

Susiarjo et al. also observed high rates of unusual configurations where non-homologous chromosomes were associated end to end.

Chromosome abnormalities

Adapted from Susiarjo et al.

 

Normal synapsis

Incomplete synapsis

The micrograph above on the left shows two pairs of chromosomes during synapsis. The pairs are intertwined tightly and the parallel arms can't be distinguished. The arrow in the micrograph on the right is pointing toward an example of incomplete synapsis, where the homologous pairs did not come together.

Micrographs from Susiarjo et al.

Using stains to identify sites on the chromosomes where recombination had occurred, Susiarjo et al. found that BPA-exposed eggs had significantly higher rates of recombination than controls (p < 0.0001).   The micrograph to the right shows two examples of unusual end-to- end associations. End-to-end associations

To confirm this, Susiarjo et al. conducted a separate study in which they dosed pregnant females as before and then examined chromosomes during meiosis for cross-over breaks, or chiasmata. As predicted by the increased rates of recombination, they found BPA-exposed eggs had more cross-overs (p < 0.05).

The large number of chromosomal errors they observed led Susiarjo et al. to predict that eggs of females exposed in the womb should have higher rates of aneuploidy in their eggs and fertilized embryos. To test the prediction they carried out another set of exposure experiments, as before.

They divided these females (exposed in the womb) into two groups. In one, they examined the females' eggs, once those females reached the age of 4-5 weeks. The other group of females were mated with normal males and the embryos were evaluated for aneuploidy. Their data revealed that as many as 40% of eggs and embryos from females exposed to BPA in utero may be chromosomally abnormal. In contrast, the rate of aneuploidy in eggs and embryos of laboratory mice is normally less than 1%. The difference is highly significant (p < 0.001).

The experiments with estrogen receptor (ER) knockout mice showed that females without functional copies of ERα were just as sensitive to BPA as normal mice, indicating that BPA, for this effect, is not working through ERα. The results with ERß, however, were surprising. They found that unexposed ERß mice suffered from the same chromosomal errors as wild type mice exposed to BPA. This indicates that the mechanism by which BPA causes these errors may that BPA, instead of behaving as an estrogen mimic in this causal pathway, instead is blocking the action of genes under the control of ERß.

What does it mean? This is the second series of experiments to demonstrate that very low doses of bisphenol A cause chromosome errors during cell division in the formation of mouse eggs. The first showed that eggs exposed in adult females become aneuploid, i.e., that the effect is from one generation to the next. The results presented in this study by Susiarjo et al. show a second generation effect: chromosomal aberrations in the eggs of daughters exposed in the womb, leading to chromosomally abnormal grandchildren. The two effects are mediated by different mechanisms.

Exposure to bisphenol A is extremely widespread. Data from people document levels in serum and amniotic fluid in the parts per billion range, comparable to the doses used in this experiment. Recent CDC data show that 95% of Americans are exposed to BPA. While the measurements used (in urine) don't permit direct comparison with this experiment, they suggest that exposures to BPA at levels comparable to these are widespread in the American public. One study has been published showing an association between BPA, aneuploidy and miscarriage in people. Very little additional epidemiological information is available.

This study adds to the growing list of over 100 studies that now document adverse effects of BPA exposure at levels beneath the EPA and FDA's current safety threshold of 50 µg/kg of body weight per day. That level is based on data obtained in the mid-1980s, based on a study showing weight loss at 50 milligrams/kg. This new study, documenting highly adverse effects extending over 3 generations, should compel a reassessment of the risks of BPA.

 

 

 
   
   

 

 

 

OSF Home
 About this website
Newest
Book Basics
  Synopsis & excerpts
  The bottom line
  Key points
  The big challenge
  Chemicals implicated
  The controversy
  Recommendations
New Science
  Broad trends
  Basic mechanisms
  Brain & behavior
  Disease resistance
  Human impacts
  Low dose effects
  Mixtures and synergy
  Ubiquity of exposure
  Natural vs. synthetic
  New exposures
  Reproduction
  Wildlife impacts
Recent Important    Results
Consensus
News/Opinion
Myths vs. Reality
Useful Links
Important Events
Important Books
Other Sources
Other Languages
About the Authors
 
Talk to us: email