Effects of the interaction between endocrine disruptor exposure and genetic polymorphisms on childhood obesity and neurodevelopmental disorders
- Autores: Viviana Ramírez López
- Directores de la Tesis: Ana María Rivas Velasco (codir. tes.), María Jesús Álvarez Cubero (codir. tes.)
- Lectura: En la Universidad de Granada ( España ) en 2025
- Idioma: inglés
- ISBN: 9788411957793
- Número de páginas: 198
- Títulos paralelos:
- Efectos de la interacción entre la exposición a disruptores endocrinos y polimorfismos genéticos en obesidad infatil y trastornos del neurodesarrollo
- Tribunal Calificador de la Tesis: Maria del Mar Larrosa Pérez (presid.), Jesús Lozano Sánchez (secret.), Sylvain Merel (voc.)
- Programa de doctorado: Programa de Doctorado en Nutrición y Ciencias de los Alimentos por la Universidad de Granada
- Materias:
- Enlaces
- Tesis en acceso abierto en: DIGIBUG
- Resumen
The global prevalence of overweight and obesity - together known as excess weight - represents a major public health problem, given the marked increase observed in recent decades. The aetiology of obesity is complex and multifactorial, involving a combination of multiple risk factors, of which genetic and environmental factors are the main focus of this Doctoral Thesis. Polygenic obesity represents the most prevalent form of obesity. In these terms, genome wide association studies (GWAS) have uncovered hundreds of single nucleotide polymorphisms (SNPs) as the most common inherited genetic variations associated with body mass index (BMI) heritability, although they account for approximately 6 % of BMI variability. At the level of environmental exposure, the obesogenic activity of endocrine disrupting chemicals (EDCs) has been highlighted due to their capacity to disrupt normal developmental and homeostatic controls over adipogenesis and energy balance. The most widely recognised EDCs include metal(loid)s, bisphenols, and parabens.
A growing body of evidence has highlighted the strong link between obesity and neurodevelopmental disorders (NDDs), including attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and intellectual disability, among others. The genetic component and EDCs-related neurodisruptive activity have emerged as key interconnected components in the bidirectional link between excess weight and NDDs. Therefore, the general objective of this Doctoral Thesis was to study the influence of different genetic polymorphisms on childhood excess weight and neurodevelopmental functioning according to the level of exposure to EDCs in the school-aged population.
A total of 351 Spanish children aged 3-12 years old were recruited from different elementary schools and primary care centres. Anthropometric data, neurodevelopment assessment tests, food frequency questionnaires (FFQs), buccal swabs, urine and hair samples were collected from each participant.
Firstly, a gene panel was designed that included multiple SNPs in hormone receptor genes, detoxification enzyme genes and genes associated with the excess weight phenotype and neurodevelopmental disorders. Gene panel consisted of: 7 polymorphisms of genes involved in the detoxification (GSTP1, GCLM) and transport system of metal(loid)s (ATP7B, ABCC2); 13 polymorphisms of candidates genes responsible for obesity-related pathways (FTO, TCF7L2, INSIG2, SH2B1, LEPR, SOD2, ADIPOQ, MC4R, IL6, ADRB2, BDNF); 6 genetic variants of metabolising enzyme encoding genes (COMT, GSTP1, CYP2C19, PON1, GPX1); 11 SNPs within genes encoding hormone receptors and nuclear transcription factors (PPARG, ESR1, AR, ESR2, TSHR, AHR, THRA, THRB); and 10 genetic polymorphisms associated with neurodevelopmental processes (BDNF/NTRK2, HTR2A, MTHFR, OXTR, SLC6A2, SNAP25). SNP genotyping assays were performed through global screening array (GSA) microchip technology and quantitative PCRs (qPCRs) with Taqman® probes.
For chemical determination of EDCs in biological samples, ten metal(loid)s were analysed in urine samples through Inductively coupled plasma mass spectrometry (ICP-MS). Levels of bisphenols and parabens in urine and hair were used to assess short- and long-term exposure, respectively, via ultra high-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry (UHPLC-MS/MS) system. And dietary exposure to bisphenols was estimated from FFQs and bisphenol content in food samples by UHPLC-MS/MS system.
In the first genetic association analysis, GSTP1 rs1695 and ATP7B rs1061472 showed significant effects on excess weight increase in those children carrying two copies of the risk G allele and being highly exposed to chromium and lead. Conversely, GCLM rs3789453 and ATP7B rs1801243 appeared to play a protective role against excess weight in those exposed to copper and lead. These findings provide the first proof that SNP effect depended on the level of exposure.
SNP-by-exposure interactions on excess weight were also identified in models stratified by bisphenol and paraben exposure according to urinary and hair levels. Firstly, the LEPR rs9436303 emerged as a relevant risk variant for excess weight, and this effect persisted across exposure-stratified models. In long-term exposure analyses, GPX1 rs1050450 was associated with increased excess weight at low single exposure to parabens, whereas LEPR rs1137101 exhibited a protective function in those highly co-exposed to bisphenols and parabens. ESR2 rs3020450 and CYP2C19 rs4244285 were identified as predisposing variants at low and high co-exposure, respectively. In short-term exposure, a higher likelihood of overweight and obesity was observed for INSIG2 rs7566605 at high bisphenol exposure and for GSTP1 rs1695 and GPX1 rs1050450 at low levels. Under situation of low and medium co-exposure, SH2B1 rs7498665 and MC4R rs17782313 displayed a protective effect, whereas ESR2 rs3020450 maintained its role in favour of excess weight. The findings reiterate the significance of considering the genetic susceptibility in the presence of exposure to environmental agents.
In the context of childhood cognitive functions assessed by the Weschler Intelligence Scale for Childre-Fifth Edition (WISC-V) Spanish form, BDNF rs11030101-T and SNAP25 rs363039-A allele carriers scored better on the fluid reasoning domain, except for those inheriting the BDNF rs6265-A allele, who had lower scores. Secondly, consistent associations of BDNF rs11030101, NTRK2 rs2289656/rs10868235, MTHFR rs1801133, HTR2A rs7997012, OXTR rs53576, and SLC6A2 rs998424 with verbal comprehension, working memory and fluid reasoning domains were obtained in the presence of dietary bisphenol exposure, resulting in relevant SNP-bisphenol interactions.
Lastly, in order to assess the safety of dietary exposure to bisphenols, in particular to bisphenol A (BPA) in vulnerable populations, a comprehensive risk assessment was performed focusing on the provisional tolerable daily intake (TDI) of 200 ng/kg bw/day derived by the German Federal Institute for Risk Assessment (BfR). For this purpose, 213 children (3-9 years), 281 adolescents (10-17 years), and 122 adults (18-39 years) were included. In a probabilistic approach, exposure data were transferred to a log-normal distribution and combined with the data on hazard characterisation using the APROBA-Plus tool. The results demonstrated that children were higher exposed to BPA compared to adolescents and adults. About 50% of the children exceeded the BfR's TDI. Consequently, BPA exposure close to the BfR's TDI may be of special concern for the child population and may serve as a basis for BPA risk assessment.
In conclusion, the works presented in this Doctoral Thesis emphasise the significance of investigating the genetic variability across pivotal mechanistic biological pathways related to exposure to EDCs and disease development, especially during critical periods such as childhood. The exploration of the genetic background and the environmental dynamics could help to fill the current knowledge gaps in the complex polygenic and multifactorial aetiology of excess weight and neurodevelopmental outcomes. In view of the lack of studies examining the impact of gene-EDCs interactions, it is argued here that genetics and EDCs exposure should be considered as interactive factors rather than individual modulators of excess weight and neurodevelopmental disabilities.
