Bisphenol A

Background

Bisphenol A (BPA) is an industrial chemical widely used as a monomer in the production of polycarbonate plastics and epoxy resins. First synthesized in 1891, BPA’s estrogenic properties were identified in the 1930s, but its widespread use in consumer products began in the 1950s. Polycarbonate plastics, known for their durability and clarity, are used in items such as reusable food and drink containers. Epoxy resins are commonly applied as protective linings inside metal food and beverage cans and in water supply pipes. BPA can also be found in thermal paper, such as that used for receipts.

Biological Basis

BPA is classified as an endocrine-disrupting chemical (EDC) because it can interfere with the body’s endocrine system. Its primary biological mechanism involves mimicking the structure and function of natural hormones, particularly estrogen. BPA can bind to estrogen receptors (ERα and ERβ) in cells, potentially activating or blocking hormonal pathways. Beyond estrogen receptors, research indicates that BPA may also interact with other hormone receptors, including androgen receptors, thyroid hormone receptors, and peroxisome proliferator-activated receptor gamma (PPARγ), thereby influencing a broad spectrum of physiological processes. The body typically metabolizes BPA through glucuronidation and sulfation in the liver, facilitating its excretion.

Clinical Relevance

Extensive research has investigated the potential health implications of BPA exposure. Studies have explored associations between BPA and various clinical outcomes, including reproductive and developmental effects such as altered fetal development, reduced fertility, and early onset of puberty. It has also been linked to metabolic disorders, including an increased risk of obesity, insulin resistance, and type 2 diabetes. Cardiovascular disease, neurodevelopmental issues, and certain hormone-sensitive cancers are additional areas of ongoing scientific inquiry. Human exposure primarily occurs through diet, as BPA can leach from plastic containers and can linings into food and beverages. Dermal contact and inhalation are also potential routes of exposure. Urinary BPA levels are frequently measured to assess human exposure.

Social Importance

The pervasive use of BPA and concerns regarding its potential health effects have garnered significant public attention and prompted regulatory actions globally. Several countries and regions have implemented restrictions or bans on BPA in specific products, particularly those intended for infants and young children, such as baby bottles and sippy cups. These regulatory shifts and public awareness have driven consumer demand for “BPA-free” alternatives across a range of products. The scientific community continues to conduct research to further elucidate BPA’s effects, establish safe exposure limits, and identify viable alternatives, contributing to ongoing public health debates and policy discussions.

Limitations

Methodological and Statistical Considerations

The statistical power of these genome-wide association studies (GWAS) is often limited by moderate sample sizes, increasing the susceptibility to false negative findings and hindering the detection of genetic associations with subtle effects. This constraint implies that genetic variants contributing a small but significant proportion to phenotypic variation may be overlooked, leading to an incomplete understanding of a trait’s genetic architecture. Furthermore, the inherent multiple testing burden in GWAS necessitates stringent statistical significance thresholds, which can inadvertently mask true associations that do not reach these high bars. ^[1]

A significant challenge for interpreting GWAS findings is the frequent lack of consistent replication across independent cohorts. This can arise from initial false positive discoveries, insufficient statistical power in replication studies, or variations in cohort characteristics that modulate genotype-phenotype associations. Without robust replication, the confidence in reported genetic associations remains tentative, impeding their translation into reliable biological insights and clinical applications. ^[1]The scope of genetic variants captured by array-based GWAS is inherently limited, as these platforms only assay a subset of all single nucleotide polymorphisms (SNPs) in the human genome, particularly those within HapMap. This partial coverage means that certain genes or functional variants not in strong linkage disequilibrium with genotyped SNPs may be missed. Consequently, GWAS data alone may not be sufficient for comprehensive investigation of candidate genes, potentially overlooking crucial regulatory or coding regions.^[2]

Population Specificity and Phenotype Characterization

The generalizability of findings from these studies is restricted by the demographic characteristics of the cohorts, which are predominantly composed of individuals of white European descent, often within specific age ranges (e.g., middle-aged to elderly). This raises concerns about the applicability of observed genetic associations to younger populations or individuals from diverse ancestral backgrounds. Additionally, participation biases, such as those introduced by recruiting volunteers or specific populations like twins, may lead to findings that are not representative of the broader general population. ^[1]

Further limitations stem from phenotype assessment methods, particularly when traits are averaged across multiple examinations spanning extended periods. Such long-term averaging can obscure age-dependent genetic effects and introduce misclassification due to evolving measurement protocols or changes in echocardiographic equipment over time. Moreover, the decision to perform only sex-pooled analyses may overlook sex-specific genetic associations, potentially missing variants that exert effects exclusively in males or females, thereby providing an incomplete picture of trait etiology. ^[2]

Unexplored Interactions and Remaining Knowledge Gaps

These studies generally did not comprehensively investigate gene-environment (GxE) interactions, which are critical for fully understanding the multifactorial nature of complex traits. Genetic variants often exert their effects in a context-specific manner, with their expression modulated by environmental factors such as diet or lifestyle. The absence of such analyses means that potential GxE interactions, which could significantly influence phenotype expression and disease risk, remain largely undetected, thereby limiting a holistic understanding of how genetic predispositions interact with external influences.^[2]

Despite identifying various genetic associations, a substantial portion of the heritability for complex traits often remains unexplained, a phenomenon referred to as “missing heritability.” This gap may arise from the limitations of current GWAS arrays in capturing all causal variants, the complex interplay of rare variants, or the unquantified contributions of gene-environment interactions. A fundamental challenge for future research involves effectively prioritizing associated SNPs for functional follow-up and integrating diverse data types to bridge these remaining knowledge gaps and more fully elucidate the genetic architecture of these traits. ^[1]

Variants

The genetic variant *rs6855040 * is located within the region of the QDPR gene and near the RPS7P6 pseudogene. The QDPRgene provides instructions for making quinoid dihydropteridine reductase, an enzyme crucial for recycling tetrahydrobiopterin (BH4), a vital cofactor involved in the synthesis of neurotransmitters like dopamine and serotonin, as well as nitric oxide production. A variation like*rs6855040 * within or near QDPR could potentially influence the enzyme’s efficiency or expression, thereby altering BH4 levels and impacting these critical biochemical pathways. ^[3]Such changes might affect an individual’s neurodevelopmental processes and susceptibility to conditions linked to neurotransmitter imbalances, potentially modulating responses to environmental factors, including exposure to endocrine disruptors.

The pseudogene RPS7P6 is a non-coding DNA sequence that resembles the functional RPS7 gene, which encodes a ribosomal protein essential for protein synthesis. While pseudogenes typically do not produce functional proteins, they can sometimes play regulatory roles, for instance, by influencing the expression of their functional counterparts or acting as decoys for microRNAs. ^[3] The presence of *rs6855040 * in proximity to RPS7P6suggests a possible, though indirect, influence on cellular processes, which might broadly affect cellular stress responses or metabolic efficiency. Environmental compounds like bisphenol A (BPA) can disrupt various cellular functions, and genetic variations in regulatory regions could modify the cellular response to such exposures, impacting how the body handles xenobiotics.

Another significant variant, *rs6974062 *, is associated with the MRPL42P4 and EPS15P1 pseudogenes. MRPL42P4 is a pseudogene related to mitochondrial ribosomal protein L42, which is fundamental for protein production within mitochondria, the cell’s powerhouses. Mitochondrial function is critical for energy metabolism and overall cellular health, and disruptions can lead to a range of physiological issues. ^[3]Given that bisphenol A (BPA) is known to interfere with mitochondrial activity and energy production, a variant affecting the regulation of mitochondrial components, even indirectly through a pseudogene, could influence how cells cope with BPA-induced metabolic stress and toxicity, potentially impacting an individual’s metabolic resilience.

The EPS15P1 pseudogene is related to EPS15, a gene involved in endocytosis, the process by which cells internalize substances from their surroundings, and in signal transduction pathways, particularly those initiated by growth factor receptors. Efficient endocytosis and proper signaling are essential for cellular communication and response to external stimuli. ^[3] *rs6974062 * could potentially impact the regulatory landscape around EPS15P1, subtly influencing endocytic processes or signaling cascades. Such an effect might alter how cells interact with, internalize, and respond to environmental endocrine disruptors like bisphenol A, which often mimic hormones and interfere with cellular signaling to exert their effects on development and metabolism.

Key Variants

RS ID	Gene	Related Traits
rs6855040	RPS7P6 - QDPR	bisphenol a measurement
rs6974062	EPS15P1 - MRPL42P4	bisphenol a measurement

Clinical Relevance

References

[1] Benjamin, Emelia J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, 2007, p. S10.

[2] Vasan, Ramachandran S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Medical Genetics, vol. 8, 2007, p. S2.

[3] Reiner AP, et al. Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet. PMID: 18439552