Bisphenol A (BPA) is an organic compound that was first synthesized by Aleksandr Dianin, a Russian chemist from St. Petersburg, in 1891. The chemical nomenclature of BPA is 2,2-bis (4-hydroxyphenyl) propane. The significance of this synthesized compound did not receive much attention until 1936, when two biochemists interested in endocrinology, Edward Dodds and William Lawson, discovered its ability to act as an estrogen agonist in ovariectomized, estrogen-deficient rats. Biochemists and endocrinologists found the results of Dodd and Lawson's experiment to be particularly important because at that early stage of research into hormones, it was still difficult to isolate naturally occurring hormones. Since then, BPA has proven to have complex developmental effects, but it has taken many researchers to sort out the details.
In the US, one in 1000 births is affected by neural tube defects (NTD). A neural tube defect is a birth defect involving the malformation of body features associated with the brain and spinal cord. An NTD originates from and is characterized by incomplete closure of the neural tube, which is an organizer and precursor of the central nervous system. In humans, incomplete closure of the neural tube during embryonic development results in anatomical abnormalities such as anencephaly (a severe lack of skull and brain), hydranencephaly (cerebral hemispheres replaced with sacs of cerebrospinal fluid), spina bifida occulta (incompletely closed lower spinal cord), iniencephaly (severe retroflexed head and spinal defects), and encephalocele (a sac-like protrusion from an opening somewhere along the midline of the skull).
Estrogen plays a key role in the regulation of gene transcription. This is accomplished by its ability to act as a ligand and to bind to specific estrogen receptor (ER) molecules, such as ERα and ERβ, which act as nuclear transcription factors. There are three major nuclear estrogen receptor protein domains: the estrogen binding domain, the protein interaction domain, and the DNA binding domain. The domain responsible for the regulation of transcription is the DNA binding domain, which binds to DNA sequences called estrogen-responsive elements (EREs), found in enhancer regions of specific genes. By the binding of estrogen or an estrogen mimic to these enhancers, the target genes become activated and the proteins produced are involved in numerous cellular processes. With an estrogen mimic or xenoestrogen, such as diethylstilbestrol (DES), the negative regulation of certain genes during embryonic development can be devastating to the developing anatomy, especially the reproductive system.
Embryogenesis is an intricate process that can easily be disrupted by means of teratogenic agents. Some of these agents target the embryonic period's "window of susceptibility," three to eight weeks after a pregnant woman's last menstruation, when the highest degree of sensitivity to embryonic cell differentiation and organ formation occurs. The embryonic period or critical period is when most organ systems form, whereas the fetal period, week eight to birth, involves the growth and modeling of the organ systems. During the window of susceptibility, teratogens such as thalidomide can severely damage critical milestones of embryonic development.
Molecular Epigenetics and Development: Histone Conformations, DNA Methylation and Genomic Imprinting
Introduced by Conrad Hal Waddington in 1942, the concept of epigenetics gave scientists a new paradigm of thought concerning embryonic development, and since then has been widely applied, for instance to inheritable diseases, molecular technologies, and indeed the human genome as a whole. A genome contains an embedded intricate coding template that provides a means of genetic expression from the initial steps of embryonic development until the death of the organism. Within the genome there are two prominent components: coding (exons) and non-coding (introns) sequences. Exons provide coding by transcribing a gene into a protein, while introns do not have this capacity. On top of these coding sequences lie mechanisms that dictate the overall capability of a gene without changing the underlying nucleotide sequence of DNA; these mechanisms are primarily known as epigenetic factors.
In 1914 Albert Niemann, a German pediatrician who primarily studied infant metabolism, published a description of an Ashkenazi Jewish infant with jaundice, nervous system and brain impairments, swollen lymph nodes (lymphadenopathy), and an enlarged liver and spleen (hepatosplenomegaly). He reported that these anatomical disturbances resulted in the premature death of the child at the age of eighteen months. After extensively studying the abnormal characteristics of the infant, Niemann came to the conclusion that the disease was a variant of Gaucher's disease. Gaucher's disease, described by the French dermatologist Philippe Gaucher in 1882, is a lipid storage disorder resulting in an excessive accumulation of lipids in the spleen, kidneys, liver, lungs, bone marrow, and brain. Niemann was able to connect the infant's disease to Gaucher's disease because it displayed similar symptoms: a noticeable accumulation of fatty substances in the brain, liver, and spleen.