RESUMO
Perfluorooctane sulfonic acid (PFOS) is a long-chain per- and polyfluoroalkyl substance (PFAS), a persistent organic pollutant, which has been used in aqueous film-forming foams. Emerging epidemiological evidence indicates a significant body burden of PFOS is observed in the lungs. Furthermore, developmental PFOS exposure dysregulates lung development and exacerbates eosinophilic inflammation, which are critical risk factors for asthma. However, it is unknown whether PFOS exerts sex-dependent effects on house dust mite (HDM) induced asthmatic progression and allergic inflammation. In this study, timed pregnant Balb/cJ dams were dosed orally via PFOS (1.0 mg/kg/d) spiked or vehicle control mealworms from gestational day (GD) 0.5 to postnatal day (PND) 21. Subsequently, HDM (30 µg/day) was administered starting at PND 77-82 for 10 days, and the mice were sacrificed 48 h after their final treatment. The serum and lung PFOS concentrations were 3.391 ± 0.189 µg/mL and 3.567 ± 0.1676 µg/g in the offspring, respectively. Male mice exposed to PFOS + HDM showed higher total cell counts in bronchoalveolar lavage fluid (BALF), macrophage counts, and eosinophil counts compared to mice exposed to HDM alone. Female mice exposed to PFOS + HDM had increased BALF eosinophil percentage, mucous production, alternatively activated (M2) macrophage polarization, and M2-associated gene expression compared to female mice exposed to HDM alone. PFOS exposure had no significant effect on HDM-induced IL-4, IL-5, or IL-13, but RANTES was further elevated in female mice. Overall, our data suggest that developmental PFOS exposure increased the risk of exacerbated eosinophilic inflammation and M2 polarization, which were more severe in female mice, suggesting sex-dependent developmental effects of PFOS on allergic airway responses.
Assuntos
Ácidos Alcanossulfônicos , Fluorocarbonos , Camundongos Endogâmicos BALB C , Pyroglyphidae , Animais , Fluorocarbonos/toxicidade , Ácidos Alcanossulfônicos/toxicidade , Camundongos , Feminino , Masculino , Pyroglyphidae/imunologia , Poluentes Ambientais/toxicidade , Gravidez , Hipersensibilidade/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Líquido da Lavagem Broncoalveolar , Asma/imunologia , Asma/induzido quimicamenteRESUMO
Although toxicology uses animal models to represent real-world human health scenarios, a critical translational gap between laboratory-based studies and epidemiology remains. In this study, we aimed to understand the toxicoepigenetic effects on DNA methylation after developmental exposure to two common toxicants, the phthalate di(2-ethylhexyl) phthalate (DEHP) and the metal lead (Pb), using a translational paradigm that selected candidate genes from a mouse study and assessed them in four human birth cohorts. Data from mouse offspring developmentally exposed to DEHP, Pb, or control were used to identify genes with sex-specific sites with differential DNA methylation at postnatal day 21. Associations of human infant DNA methylation in homologous mouse genes with prenatal DEHP or Pb were examined with a meta-analysis. Differential methylation was observed on 6 cytosines (adjusted-p < 0.05) and 90 regions (adjusted-p < 0.001). This translational approach offers a unique method that can detect conserved epigenetic differences that are developmentally susceptible to environmental toxicants.
Assuntos
Metilação de DNA , Epigênese Genética , Chumbo , Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Humanos , Lactente , Masculino , Camundongos , Gravidez , Dietilexilftalato/toxicidade , Metilação de DNA/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Epigênese Genética/efeitos dos fármacos , Chumbo/toxicidade , Ácidos Ftálicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamenteRESUMO
OBJECTIVE: To investigate the prospective associations of life-course perfluoroalkyl substances (PFASs) exposure with glucose homeostasis at adulthood. METHODS: We calculated insulin sensitivity and beta-cell function indices based on 2-h oral glucose tolerance tests at age 28 in 699 Faroese born in 1986-1987. Five major PFASs were measured in cord whole blood and in serum from ages 7, 14, 22, and 28 years. We evaluated the associations with glucose homeostasis measures by PFAS exposures at different ages using multiple informant models fitting generalized estimating equations and by life-course PFAS exposures using structural equation models. RESULTS: Associations were stronger for perfluorooctane sulfonate (PFOS) and suggested decreased insulin sensitivity and increased beta-cell function-for example, ß (95% CI) for log-insulinogenic index per PFOS doublingâ =â 0.12 (0.02, 0.22) for prenatal exposures, 0.04 (-0.10, 0.19) at age 7, 0.07 (-0.07, 0.21) at age 14, 0.05 (-0.04, 0.15) at age 22, and 0.04 (-0.03, 0.11) at age 28. Associations were consistent across ages (P for age interactionâ >â 0.10 for all PFASs) and sex (P for sex interactionâ >â 0.10 for all PFASs, except perfluorodecanoic acid). The overall life-course PFOS exposure was also associated with altered glucose homeostasis (Pâ =â 0.04). Associations for other life-course PFAS exposures were nonsignificant. CONCLUSIONS: Life-course PFAS exposure is associated with decreased insulin sensitivity and increased pancreatic beta-cell function in young adults.
Assuntos
Glicemia/metabolismo , Exposição Ambiental , Poluentes Ambientais/toxicidade , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/efeitos dos fármacos , Adolescente , Adulto , Ácidos Alcanossulfônicos/sangue , Ácidos Alcanossulfônicos/toxicidade , Caprilatos/sangue , Caprilatos/toxicidade , Criança , Ácidos Decanoicos/sangue , Ácidos Decanoicos/toxicidade , Poluentes Ambientais/sangue , Ácidos Graxos , Feminino , Fluorocarbonos/sangue , Fluorocarbonos/toxicidade , Teste de Tolerância a Glucose , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Ácidos Sulfônicos/sangue , Ácidos Sulfônicos/toxicidade , Adulto JovemRESUMO
The consequences of damage to the mitochondrial genome (mtDNA) are poorly understood, although mtDNA is more susceptible to damage resulting from some genotoxicants than nuclear DNA (nucDNA), and many environmental toxicants target the mitochondria. Reports from the toxicological literature suggest that exposure to early-life mitochondrial damage could lead to deleterious consequences later in life (the "Developmental Origins of Health and Disease" paradigm), but reports from other fields often report beneficial ("mitohormetic") responses to such damage. Here, we tested the effects of low (causing no change in lifespan) levels of ultraviolet C (UVC)-induced, irreparable mtDNA damage during early development in Caenorhabditis elegans. This exposure led to life-long reductions in mtDNA copy number and steady-state ATP levels, accompanied by increased oxygen consumption and altered metabolite profiles, suggesting inefficient mitochondrial function. Exposed nematodes were also developmentally delayed, reached smaller adult size, and were rendered more susceptible to subsequent exposure to chemical mitotoxicants. Metabolomic and genetic analysis of key signaling and metabolic pathways supported redox and mitochondrial stress-response signaling during early development as a mechanism for establishing these persistent alterations. Our results highlight the importance of early-life exposures to environmental pollutants, especially in the context of exposure to chemicals that target mitochondria.
Assuntos
Caenorhabditis elegans , Dano ao DNA , Animais , Caenorhabditis elegans/genética , DNA Mitocondrial/metabolismo , Mitocôndrias/metabolismo , OxirreduçãoRESUMO
Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within PDGFRL associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within TRHR with tibia bone Pb (adjusted P-value < .05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted P-value < .05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific.
RESUMO
PURPOSE OF REVIEW: We reviewed and summarized the epidemiological evidence for the influence that pre- and postnatal exposures to perfluoroalkyl substances (PFASs) may have on health outcomes in offspring, with a particular focus on birth outcomes and postnatal growth, immunomodulatory effects and neurodevelopment. RECENT FINDINGS: PFASs are persistent organic pollutants that have been widely produced and used in a range of commercial products since the 1950s. Human exposures to PFASs are nearly ubiquitous globally, but studies that addressed potential health effects of PFASs have only begun to accumulate in recent years. Animal studies suggest adverse effects resulting from developmental encompasses prenatal exposures to PFASs. In humans, the developing fetus is exposed to PFASs via active or passive placenta transfer, while newborns might be exposed via breastfeeding or PFAS in the home environment. Overall, epidemiological findings are consistent and suggest possible associations with fetal and postnatal growth and immune function, while the findings on neurodevelopmental endpoints to date are rather inconclusive. Methodological challenges and future directions for PFASs-focused research are discussed.
Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Fluorocarbonos/toxicidade , Hipersensibilidade/etiologia , Animais , Doenças Autoimunes/induzido quimicamente , Feminino , Feto/efeitos dos fármacos , Humanos , Sistema Imunitário/efeitos dos fármacos , Recém-Nascido , GravidezRESUMO
Exposures to bisphenol-A, a weak estrogenic chemical, largely used for the production of plastic containers, can affect the rodent behaviour. Thus, we examined the relationships between bisphenol-A and the anxiety-like behaviour, spatial skills, and aggressiveness, in 12 toxicity studies of rodent offspring from females orally exposed to bisphenol-A, while pregnant and/or lactating, by median and linear splines analyses. Subsequently, the meta-regression analysis was applied to quantify the behavioural changes. U-shaped, inverted U-shaped and J-shaped dose-response curves were found to describe the relationships between bisphenol-A with the behavioural outcomes. The occurrence of anxiogenic-like effects and spatial skill changes displayed U-shaped and inverted U-shaped curves, respectively, providing examples of effects that are observed at low-doses. Conversely, a J-dose-response relationship was observed for aggressiveness. When the proportion of rodents expressing certain traits or the time that they employed to manifest an attitude was analysed, the meta-regression indicated that a borderline significant increment of anxiogenic-like effects was present at low-doses regardless of sexes (ß)=-0.8%, 95% C.I. -1.7/0.1, P=0.076, at ≤120 µg bisphenol-A. Whereas, only bisphenol-A-males exhibited a significant inhibition of spatial skills (ß)=0.7%, 95% C.I. 0.2/1.2, P=0.004, at ≤100 µg/day. A significant increment of aggressiveness was observed in both the sexes (ß)=67.9,C.I. 3.4, 172.5, P=0.038, at >4.0 µg. Then, bisphenol-A treatments significantly abrogated spatial learning and ability in males (P<0.001 vs. females). Overall, our study showed that developmental exposures to low-doses of bisphenol-A, e.g. ≤120 µg/day, were associated to behavioural aberrations in offspring.