Bisphenol A severely disrupts fetal epigenetics

Water bottle containing bisphenol A

The most controversial chemical compound bisphenol A is found in many plastics, including sometimes those used as food or water containers. This study adds to the long list of known harms of this chemical, which nevertheless remains widely allowed.

Martha Susiarjo et al., Bisphenol A Exposure Disrupts Genomic Imprinting in the Mouse. PLoS Genetics 2013. Open access → LINK [doi:10.1371/journal.pgen.1003401]

Abstract

Exposure to endocrine disruptors is associated with developmental defects. One compound of concern, to which humans are widely exposed, is bisphenol A (BPA). In model organisms, BPA exposure is linked to metabolic disorders, infertility, cancer, and behavior anomalies. Recently, BPA exposure has been linked to DNA methylation changes, indicating that epigenetic mechanisms may be relevant. We investigated effects of exposure on genomic imprinting in the mouse as imprinted genes are regulated by differential DNA methylation and aberrant imprinting disrupts fetal, placental, and postnatal development. Through allele-specific and quantitative real-time PCR analysis, we demonstrated that maternal BPA exposure during late stages of oocyte development and early stages of embryonic development significantly disrupted imprinted gene expression in embryonic day (E) 9.5 and 12.5 embryos and placentas. The affected genes included Snrpn, Ube3a, Igf2, Kcnq1ot1, Cdkn1c, and Ascl2; mutations and aberrant regulation of these genes are associated with imprinting disorders in humans. Furthermore, the majority of affected genes were expressed abnormally in the placenta. DNA methylation studies showed that BPA exposure significantly altered the methylation levels of differentially methylated regions (DMRs) including the Snrpn imprinting control region (ICR) and Igf2 DMR1. Moreover, exposure significantly reduced genome-wide methylation levels in the placenta, but not the embryo. Histological and immunohistochemical examinations revealed that these epigenetic defects were associated with abnormal placental development. In contrast to this early exposure paradigm, exposure outside of the epigenetic reprogramming window did not cause significant imprinting perturbations. Our data suggest that early exposure to common environmental compounds has the potential to disrupt fetal and postnatal health through epigenetic changes in the embryo and abnormal development of the placenta.

 

Kerguelen mice: a model for human expansions?

I will today stop at a new genetic paper that does not deal with humans but with a not-so-distant relative: house mice. Specifically with mice in the remote Kerguelen islands, which have been known to humans (and hence to mice) only since 1772.

Emilie A. Hardouin et al., House mouse colonization patterns on the sub-Antarctic Kerguelen Archipelago suggest singular primary invasions and resilience against re-invasion. BMC Evolutionary Biology 2010. Open Access. 

Abstract (provisional)

Background

Starting from Western Europe, the house mouse (Mus musculus domesticus) has spread across the globe in historic times. However, most oceanic islands were colonized by mice only within the past 300 years. This makes them an excellent model for studying the evolutionary processes during early stages of new colonization. We have focused here on the Kerguelen Archipelago, located within the sub-Antarctic area and compare the patterns with samples from other Southern Ocean islands.

Results

We have typed 18 autosomal and six Y-chromosomal microsatellite loci and obtained mitochondrial D-loop sequences for a total of 534 samples, mainly from the Kerguelen Archipelago, but also from the Falkland Islands, Marion Island, Amsterdam Island, Antipodes Island, Macquarie Island, Auckland Islands and one sample from South Georgia. We find that most of the mice on the Kerguelen Archipelago have the same mitochondrial haplotype and all share the same major Y-chromosomal haplotype. Two small islands (Cochons Island and Cimetiere Island) within the archipelago show a different mitochondrial haplotype, are genetically distinct for autosomal loci, but share the major Y-chromosomal haplotype. In the mitochondrial D-loop sequences, we find several single step mutational derivatives of one of the major mitochondrial haplotypes, suggesting an unusually high mutation rate, or the occurrence of selective sweeps in mitochondria.

Conclusions

Although there was heavy ship traffic for over a hundred years to the Kerguelen Archipelago, it appears that the mice that have arrived first have colonized the main island (Grande Terre) and most of the associated small islands.The second invasion that we see in our data has occurred on islands which are detached from Grande Terre and were likely to have had no resident mice prior to their arrival. The genetic data suggest that the mice of both primary invasions originated from related source populations. Our data suggest that an area colonized by mice is refractory to further introgression, possibly due to fast adaptations of the resident mice to local conditions.

The abstract alone is quite explanatory.

I must say that the reason for the refraction may not be adaptations to local conditions as much as mere demographic pressure: any new mice would be automatic minority and have poor chances of perpetuation, even in the absence of adaptations. Numbers alone make the difference, proving statistically difficult for any new arrival to leave a mark after the first population is consolidated.

Another detail worth discussing is:

In the mitochondrial D-loop sequences, we find several single step mutational derivatives of one of the major mitochondrial haplotypes, suggesting an unusually high mutation rate, or the occurrence of selective sweeps in mitochondria.

The mutation rate does not look too striking to me: 200 years for mice is like 10,000 for us maybe, as they reach reproductive maturity in a matter of months. So it’s like one (or two in a few sub-lineages)  surviving mutations downstream of the founder haplotype, which is anyhow still massively dominant.

Fig.2A mtDNA HVS haplotype network

In other words: there were some distinct founder effects of some derived haplotypes, mostly in Kerguelen itself but also overseas: in Falkland and Auckland islands and even back to Europe (Britain).

The diversity of derived basal lineages clearly indicates that this Kerguelen haplotype (yellow) exploded in the islands, regardless that it may be original from mainland Africa (black) and regardless that it has also spread overseas. This in the equivalent of 10,000 human years (very roughly).

It reminds me somewhat of what we can see in Eurasian human mtDNA, with the yellow lineage resembling human mtDNA M somewhat and the magenta one like N. And that is one reason I wanted to comment this paper, really. Of course the stage of diversification and other aspects are clearly different but it does illustrates how founder effects proceed and how demic pressure alone tends to fend off new colonizations.