Predisposing risk factors for cleft lip and palate in an Amazonian population by focusing on nutritional factors: A case-control study.

BACKGROUND: Orofacial clefts (OFC) are the most common congenital malformation of the craniofacial skeleton. Attempts have been made to correlate the components of maternal diet as triggers for the development or prevention of OFC. OBJECTIVE: To analyze nutritional status as a predictive factor for the development of cleft lip and palate in an Amazonian population. METHODS: A total of 152 mothers within 3 months of delivery were interviewed for comparison: 51 mothers of children with nonsyndromic cleft lip and palate (CLP) (study group) and 101 mothers of children without OFC (control group). A food frequency questionnaire was used to assess maternal nutrition and to analyze the influence of macro- and micronutrients on the possible predisposition or protection for CLP. RESULTS: The study group showed higher percentage of lipid intake than did the control group (p = 0.01). Among the participants with no family history of OFC, the study group had a higher percentage of lipid intake (p = 0.002) and lower vegetable intake (p = 0.037). Maternal micronutrient intake among the participants with a positive family history was lower in the study group for vitamins B2 (p = 0.03), B5 (p = 0.036), E (p = 0.03), and folate (p = 0.022). CONCLUSIONS: Nutritional analysis indicated that higher maternal lipid intake increased the likelihood of having offsprings with nonsyndromic CLP. Moreover, families with a history of OFC and low maternal folate intake showed heightened risk of nonsyndromic CLP in their offsprings.

Gestational glyphosate exposure and early childhood neurodevelopment in a Puerto Rico birth cohort.

INTRODUCTION: N-(phosphonomethyl)glycine, or glyphosate, is a non-selective systemic herbicide widely used in agricultural, industrial, and residential settings since 1974. Glyphosate exposure has been inconsistently linked to neurotoxicity in animals, and studies of effects of gestational exposure among humans are scarce. In this study we investigated relationships between prenatal urinary glyphosate analytes and early childhood neurodevelopment. METHODS: Mother-child pairs from the PROTECT-CRECE birth cohort in Puerto Rico with measures for both maternal urinary glyphosate analytes and child neurodevelopment were included for analysis (n = 143). Spot urine samples were collected 1-3 times throughout pregnancy and analyzed for glyphosate and aminomethylphosphonic acid (AMPA), an environmental degradant of glyphosate. Child neurodevelopment was assessed at 6, 12, and 24 months using the Battelle Developmental Inventory, 2nd edition Spanish (BDI-2), which provides scores for adaptive, personal-social, communication, motor, and cognitive domains. We used multivariable linear regression to examine associations between the geometric mean of maternal urinary glyphosate analytes across pregnancy and BDI-2 scores at each follow-up. Results were expressed as percent change in BDI-2 score per interquartile range increase in exposure. RESULTS: Prenatal AMPA concentrations were negatively associated with communication domain at 12 months (%change = -5.32; 95%CI: 9.04, -1.61; p = 0.007), and communication subdomain scores at 12 and 24 months. At 24 months, four BDI-2 domains were associated with AMPA: adaptive (%change = -3.15; 95%CI: 6.05, -0.25; p = 0.038), personal-social (%change = -4.37; 95%CI: 7.48, -1.26; p = 0.008), communication (%change = -7.00; 95%CI: 11.75, -2.26; p = 0.005), and cognitive (%change = -4.02; 95%CI: 6.72, -1.32; p = 0.005). Similar trends were observed with GLY concentrations, but most confidence intervals include zero. We found no significant associations at 6 months. CONCLUSIONS: Our results suggest that gestational exposure to glyphosate is associated with adverse early neurodevelopment, with more pronounced delays at 24 months. Given glyphosate's wide usage, further investigation into the impact of gestational glyphosate exposure on neurodevelopment is warranted.

Long-lasting developmental effects in rat offspring after maternal exposure to acetamiprid in the drinking water during gestation.

Neonicotinoids (NNTs) are a class of insecticides proposed to be safe for pest control in urban, suburban, and agricultural applications. However, little is known about their developmental effects after repeated low-dose exposures during gestation. Here, we tested a dose considered subthreshold for maternal toxicity in rats (6 mg/kg/day) by assessing several morphological, biochemical, and neurobehavioral features in preterm fetuses and developing pups after maternal administration of the NTT acetamiprid (ACP) dissolved in the drinking water during gestational days (GD) 2-19. The exploratory evaluation included monitoring maternal body weight gain, fetal viability, body weight and sex ratio, cephalic length, neonatal body weight and sex ratio, metabolic enzymes in the placenta, maternal blood and fetal liver, and anogenital distance and surface righting response during infancy. We also used the circling training test to study the integrity of the associative-spatial-motor response in adolescence. Results showed no consistent findings indicating maternal, reproductive or developmental toxicity. However, we found ACP effects on maternal body weight gain, placental butyrylcholinesterase activity, and neurobehavioral responses, suggestive of a mild toxic action. Thus, our study showed a trend for developmental susceptibility at a dose so far considered subtoxic. Although the ACP concentration in environmental samples of surface water and groundwater has been mostly reported to be much lower than that used in our study, our results suggest that the ACP point of departure used in current guidelines aimed to prevent developmental effects may need to be verified by complementary sensitive multiple-endpoint testing in the offspring.

Integrated transcriptome and proteome analysis indicates potential biomarkers of prostate cancer in offspring of pregnant rats exposed to a phthalate mixture during gestation and lactation.

As the second leading cause of death for cancer among men worldwide, prostate cancer (PCa) prevention and detection remain a critical challenge. One aspect of PCa research is the identification of common environmental agents that may increase the risk of initiation and progression of PCa. Endocrine disrupting chemicals (EDCs) are strong candidates for risk factors, partially because they alter essential pathways for prostate gland development and oncogenesis. Phthalates correspond to a set of commercially used plasticizers that humans are exposed to ubiquitously. Here, we show that maternal exposure to a phthalate mixture interferes with the expression profile of mRNA and proteins in the ventral prostate of offspring and increases the susceptibility to prostate adenocarcinomas in aged animals. The data highlight Ubxn11, Aldoc, Kif5c, Tubb4a, Tubb3, Tubb2, Rab6b and Rab3b as differentially expressed targets in young and adult offspring descendants (PND22 and PND120). These phthalate-induced targets were enriched for pathways such as: dysregulation in post-translational protein modification (PTPM), cell homeostasis, HSP90 chaperone activity, gap junctions, and kinases. In addition, the Kif5c, Tubb3, Tubb2b and Tubb4a targets were enriched for impairment in cell cycle and GTPase activity. Furthermore, these targets showed strong relationships with 12 transcriptional factors (TF), which regulate the phosphorylation of eight protein kinases. The correlation of TF-kinases is associated with alterations in immune system, RAS/ErbB/VEGF/estrogen/HIF-1 signaling pathways, cellular senescence, cell cycle, autophagy, and apoptosis. Downregulation of KIF5C, TUBB3 and RAB6B targets is associated with poor prognosis in patients diagnosed with adenocarcinoma. Collectively, this integrative investigation establishes the post-transcriptional mechanisms in the prostate that are modulated by maternal exposure to phthalate mixture during gestation and lactation.

Investigation of the impact of AXL, TLR3, and STAT2 in congenital Zika syndrome through genetic polymorphisms and protein-protein interaction network analyses.

INTRODUCTION: Zika virus (ZIKV) is a human teratogen that causes congenital Zika syndrome (CZS). AXL, TLR3, and STAT2 are proteins involved in the ZIKV's entry into cells (AXL) and host's immune response (TLR3 and STAT2). In this study, we evaluated the role of genetic polymorphisms in these three genes as risk factors to CZS, and highlighted which proteins that interact with them could be important for ZIKV infection and teratogenesis. MATERIALS AND METHODS: We evaluate eighty-eight children exposed to ZIKV during the pregnancy, 40 with CZS and 48 without congenital anomalies. The evaluated polymorphisms in AXL (rs1051008), TLR3 (rs3775291), and STAT2 (rs2066811) were genotyped using TaqMan® Genotyping Assays. A protein-protein interaction network was created in STRING database and analyzed in Cytoscape software. RESULTS: We did not find any statistical significant association among the polymorphisms and the occurrence of CZS. Through the analyses of the network composed by AXL, TLR3, STAT2 and their interactions targets, we found that EGFR and SRC could be important proteins for the ZIKV infection and its teratogenesis. CONCLUSION: In summary, our results demonstrated that the evaluated polymorphisms do not seem to represent risk factors for CZS; however, EGFR and SRC appear to be important proteins that should be investigated in future studies.

Downregulation of Microcephaly-Causing Genes as a Mechanism for ZIKV Teratogenesis: A Meta-analysis of RNA-Seq Studies.

Zika virus (ZIKV) is a neurotropic teratogen that causes congenital Zika syndrome (CZS), characterized by brain and eye anomalies. Impaired gene expression in neural cells after ZIKV infection has been demonstrated; however, there is a gap in the literature of studies comparing whether the differentially expressed genes in such cells are similar and how it can cause CZS. Therefore, the aim of this study was to compare the differential gene expression (DGE) after ZIKV infection in neural cells through a meta-analysis approach. Through the GEO database, studies that evaluated DGE in cells exposed to the Asian lineage of ZIKV versus cells, of the same type, not exposed were searched. From the 119 studies found, five meet our inclusion criteria. Raw data of them were retrieved, pre-processed, and evaluated. The meta-analysis was carried out by comparing seven datasets, from these five studies. We found 125 upregulated genes in neural cells, mainly interferon-stimulated genes, such as IFI6, ISG15, and OAS2, involved in the antiviral response. Furthermore, 167 downregulated, involved with cellular division. Among these downregulated genes, classic microcephaly-causing genes stood out, such as CENPJ, ASPM, CENPE, and CEP152, demonstrating a possible mechanism by which ZIKV impairs brain development and causes CZS.

¿Afecta la infección asintomática, leve y moderada por Covid-19 en el primer y segundo trimestre los resultados del embarazo?

Objetivo : Determinar los efectos de la infección Covid-19 asintomática, leve y moderada en el primer y segundo trimestres en los resultados del embarazo. Métodos : El estudio se realizó en las gestantes que acudieron al Departamento de Perinatología de la Universidad de Ciencias de la Salud de Izmir entre octubre de 2021 y julio de 2022. Se registraron las mujeres embarazadas que presentaban infección asintomática, leve y moderada por Covid-19 en el 1º y 2º trimestre y se siguió el desarrollo de la gestación. Resultados : Un total de 437 pacientes participaron en el estudio. El número de pacientes asintomáticos, leves y moderados de Covid-19 fue de 142, 157 y 138, respectivamente. Cada grupo se analizó como subgrupo del 1º y 2º trimestre según el momento de la infección por Covid-19. La edad media de las pacientes con Covid-19 moderado era superior a la de las pacientes con Covid-19 leve/asintomático (p=0,021). Se observó que el índice de masa corporal era mayor en las pacientes con Covid-19 moderado que en las pacientes con infección leve/asintomática (p=0,048). El parto pretérmino (entre las semanas 34 y 37) fue significativamente mayor en los casos con infección moderada por Covid-19 (p=0,041). Este aumento ocurrió principalmente en pacientes con infección por Covid-19 en el 2º trimestre. No hubo modificaciones significativas en las tasas de cesárea, trastornos hipertensivos del embarazo, pérdida fetal, retraso del crecimiento intrauterino, colestasis del embarazo y diabetes gestacional. Conclusiones : Los efectos de la infección por Covid-19 al inicio del embarazo (1º y 2º trimestres) siguen siendo objeto de investigación. La infección moderada por Covid-19, especialmente en el 2º trimestre, puede provocar un aumento de la tasa de partos prematuros.

Objectives: To evaluate the effects of asymptomatic, mild and moderate Covid-19 infection in the 1st and 2nd trimesters on pregnancy outcomes. Material and methods: The study was performed among patients who applied to the Perinatology Department of Izmir University of Health Sciences, between October 2021 and July 2022. Pregnant women who had asymptomatic, mild and moderate Covid-19 infection in the 1st and 2nd trimesters were registered and their pregnancy processes were followed. Results: A total of 437 patients participated in the study. The numbers of asymptomatic, mild and moderate Covid-19 patients were 142, 157 and 138, respectively. Each group was analyzed as 1st and 2nd trimester subgroups according to the time of Covid-19 infection. The mean age of patients with moderate Covid-19 was higher than with mild/asymptomatic Covid-19 (p=0.021). Body mass index was found to be higher in patients with moderate Covid-19 compared to patients with mild/asymptomatic infection (p=0.048). Preterm labor (between 34th and 37th weeks) was significantly higher with moderate Covid-19 infection (p=0.041). This significant increase was mainly due to the preterm birth rate in patients with previous Covid-19 infection in the 2nd trimester. There was no significant change in the rates of cesarean section, hypertensive disorders of pregnancy, fetal loss, intrauterine growth restriction, cholestasis of pregnancy and gestational diabetes. Conclusions: The effects of Covid-19 infection in early pregnancy (1st and 2nd trimester) are still the subject of research. Moderate Covid-19 infection, especially in the 2nd trimester, may lead to an increase in the rate of preterm birth.

Effects of intrauterine exposure to SARS-CoV-2 on infants' development: a rapid review and meta-analysis.

Potential medium- and long-term neurodevelopmental sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy have not been ruled out. We aimed to systematically review and summarize the evidence regarding the effects of intrauterine exposure to SARS-CoV-2 on infant development and behavior. Scopus, PubMed, Web of Science, CINAHL, and PsycNet databases were searched for studies published up to February 6, 2023, investigating the effects of gestational SARS-CoV-2 on infant development and behavior. We performed narrative synthesis according to updated protocols. Studies using comparison groups and with the Ages and Stages Questionnaires-Third Edition (ASQ-3) scores available were included in a meta-analysis performed according to Cochrane protocols. We used the Newcastle-Ottawa Quality Assessment Scale to analyze the risk of bias. Heterogeneity was calculated using the I2 statistic. The search identified 2,782 studies. After removing duplicates and applying the eligibility criteria, we performed a narrative synthesis of 10 included studies and a meta-analysis of three. There was no evidence of higher developmental delay rates in infants exposed to SARS-CoV-2 during pregnancy compared to non-exposed infants. However, the exposed infants scored lower than either the non-exposed children or pre-pandemic cohorts in some domains. Pooled results from the random-effects model indicated that SARS-CoV-2-exposed infants had lower scores on fine motor (mean difference [MD] = -4.70, 95% confidence interval [CI]: -8.76; -0.63), and problem-solving (MD = -3.05, 95% CI: -5.88; -0.22) domains than non-exposed infants (heterogeneity: I2 = 69% and 88%, respectively). There was no difference between the exposed and non-exposed infants in the communication, gross motor, and personal-social ASQ-3 domains.  Conclusion: We did not find evidence confirming the association between SARS-CoV-2 gestational exposure and neurodevelopmental delays. However, the meta-analysis indicated that gestational exposure negatively affected fine motor and problem-solving skills. Robust evidence on this topic is still incipient, and the available studies present methodological inconsistencies that limit the drawing of clear-cut conclusions.   PROSPERO registration: #CRD42022308002; March 14, 2022. What is Known: • COVID-19 is associated with adverse pregnancy outcomes potentially linked to neurodevelopmental delays. • SARS-CoV-2 vertical transmission is rare; however, infections during pregnancy can be deleterious to the fetus, possibly mediated by maternal immune activation and other inflammatory mechanisms. What is New: • No evidence of increased developmental delay rates among SARS-CoV-2 gestational-exposed infants was found. However, a meta-analysis of three studies showed lower scores in fine motor and personal social ASQ-3 domains among exposed infants. • SARS-CoV-2 gestational exposure and the pandemic can affect child development via many mechanisms. Potential neurodevelopmental sequelae of SARS-CoV-2 exposure during gestation have not been ruled out.

Gestational lead exposure and its effects on fetal/infant development - A systematic review.

Studies suggest that gestational exposure to lead (Pb) is related to spontaneous abortions, preterm birth, lower infant birth weight and length, and neurological dysfunctions. However, the evidence about its effects during pregnancy exposure on fetal and child development is still poor. Thus, the aim of this systematic review was to verify the association between prenatal exposure to Pb and the occurrence of neurobehavioral deficits, miscarriages, and child mortality. Observational studies with pregnant women exposed to Pb during pregnancy were included, without gender or ethnicity restrictions. The MEDLINE, Cochrane Library, EMBASE, Scopus, Web of Science, and LILACS databases were searched. The reading of titles and abstracts was conducted, followed by reading in full format and data extraction, that were performed independently by two reviewers. The included studies were evaluated by Downs and Black tool and qualitatively synthesized. Certainty of evidence was assessed by Grading of Recommendations Assessment, Development, and Evaluations (GRADE). The study protocol was registered with the Prospective Registry of Systematic Reviews (PROSPERO; CRD42022296750). Among twenty-one studies included, sixteen were classified as prospective cohort, two case-control, one nested case-control, one cohort, and one longitudinal study. No study that evaluated child mortality associated with gestational Pb exposure was found. There is a very low certainty of evidence in the association of gestational Pb exposure and neurobehavioral deficits or miscarriages. This systematic review reflects the poor evidence and the challenges of human toxicology studies, since it was not possible to associate gestational Pb exposure to neurobehavioral deficits, miscarriages, and child mortality.

Reproductive toxicity of maternal exposure to di(2-ethylhexyl)phthalate and butyl paraben (alone or in association) on both male and female Wistar offspring.

Parabens and phthalates are commonly found as contaminants in human fluids and are able to provoke reproductive toxicity, being considered endocrine disruptors. To evaluate the effects of phthalate and paraben, alone or in combination, on reproductive development of the offspring, female pregnant Wistar rats were allocated in six experimental groups: Three control groups (gavage [CG], subcutaneous [CS], and gavage + subcutaneous) received corn oil as vehicle, and the remaining groups were exposed to di(2-ethylhexyl)phthalate (DEHP) (500 mg/kg, gavage), butyl paraben (BP) (100 mg/kg, subcutaneously), or MIX (DEHP + BP), from Gestational Day 12 until Postnatal Day (PND) 21. The following parameters were assessed on the offspring: anogenital distance and weight at PND 1, nipple counting at PND 13, puberty onset, estrous cycle, weights of reproductive and detoxifying organs, histological evaluation of reproductive organs, and sperm evaluations (counts, morphology, and motility). Female pups from MIX group presented reduced body weight at PND 1, lower AGD, and decreased endometrium thickness. Male animals showed decreased body weight at PND 1 and lower number of Sertoli cells on DEHP and MIX groups, MIX group revealed increase of abnormal seminiferous tubules, DEHP animals presented delayed preputial separation and higher percentage of immotile sperms, and BP males presented diminished number of Leydig cells. In conclusion, the male offspring was more susceptible to DEHP toxicity; even when mixed to paraben, the main negative effects observed seem to be due to antiandrogenic phthalate action. On the other hand, DEHP seems to be necessary to improve the effects of BP on reducing estrogen-dependent and increasing androgen-dependent events.

Contribution of miR-124 rs531564 polymorphism to the occurrence of congenital Zika syndrome.

Zika virus (ZIKV) cause Congenital Zika Syndrome (CZS) in individuals exposed during pregnancy. Studies have shown that ZIKV infection positively regulates the miR-124 expression in neural cells, which leads to a decrease of TFRC, a gene targeted of this miRNA. Both miR-124 and TFRC exhibit a pivotal role in nervous system development. Therefore, in this study we aimed to investigate whether genetic variants that affect the expression of these genes could act together with ZIKV to increase the risk of individuals developing CZS. TFRC rs406271 and MIR-124-1 rs531564 polymorphisms were genotyped, using TaqMan® Genotyping Assays, in a sample of children who were exposed to ZIKV during pregnancy, of whom 40 were born with CZS and 48 without congenital anomalies. We identified that individuals with CZS presented a higher frequency of CG genotype of rs531564 polymorphism in MIR-124-1 (p=0.048), which is associated with increased expression of miR-124. Since ZIKV also upregulates the expression of this miRNA, the presence of CG genotype in individuals exposed to the virus could lead to a scenario of overexpression of miR-124 in the brain. Since teratogenesis is a multifactorial event, this genetic finding could partly explain why such individuals are more susceptible to CZS, considering both the downregulation of important neurodevelopment genes, as well as deregulation of the neurogenesis process. Thus, we provide preliminary evidence about a possible genetic risk factor to CZS and highlight the importance of analyzing functional polymorphisms related to epigenetic modulators of neurodevelopment genes in the context of ZIKV teratogenesis.

Early exposure to agricultural pesticides and the occurrence of autism spectrum disorder: a systematic review / Exposição precoce a agrotóxicos de uso agrícola e ocorrência do transtorno do espectro autista: uma revisão sistemática

Abstract Objective: The aim of this study was to evaluate the influence of early exposure to agricultural pesticides and their relationship with autism spectrum disorder. Data source: This systematic review was registered at PROSPERO as CRD42020204842. The subject was systematically analyzed on PubMed, Scopus, and Web of Science databases until April 2021. Only studies with humans with early exposure to agricultural pesticides and diagnosis of autism were included. Exclusion criteria were studies on pesticides for domestic or veterinary use and late exposure. There were no language and time restriction. The quality analysis of the studies used the Newcastle-Ottawa Scale. Data synthesis: Six case-control studies were included; three of them measured the route of exposure by maternal biomarkers and the others by the residence address. The studies had scores between moderate and high in the quality assessment tool. It was found high rates of association between early exposure to agricultural pesticides and autism and detection limit above the quantification for a sample of polychlorinated biphenyls, hexachlorobenzene, and dichlorodiphenyldichloroethylene. Conclusions: There is evidence concerning the exposure to agricultural pesticides in early life and the development of the autism spectrum disorder; however, more studies are required to better understand their possible association.

RESUMO Objetivo: Compreender a influência da exposição precoce a agrotóxicos de uso agrícola e sua relação com o transtorno do espectro autista. Fontes de dados: Esta revisão sistemática foi registrada no banco de dados PROSPERO sob número CRD42020204842. Por meio das bases de dados PubMed, Scopus e Web of Science, o assunto foi analisado sistematicamente até abril de 2021. Foram incluídos somente estudos com humanos, sendo critérios de inclusão a exposição precoce a agrotóxicos de uso agrícola e o diagnóstico de autismo e critérios de exclusão agrotóxicos de uso doméstico ou veterinário e exposição tardia. Todos os estudos foram analisados sem restrição de linguagem e tempo. A qualidade dos estudos foi avaliada pela NewCastle Ottawa Scale. Síntese dos dados: No total, seis estudos caso-controle foram incluídos. Três deles mensuraram a exposição pelos biomarcadores maternos e os demais (50%) pelo endereço de moradia. Os trabalhos apresentaram qualidade entre moderada e alta. Encontrou-se alta taxa de associação entre a exposição precoce à agrotóxicos e o autismo e detecção acima do limite de quantificação para amostras de bifenilas policloradas, hexaclorobenzeno e diclorodifenildicloroetileno. Conclusões: Existem evidências sobre a exposição a agrotóxicos de uso agrícola precocemente e o desenvolvimento do transtorno do espectro autista, porém mais pesquisas são necessárias para melhor compreensão da associação.

Exposição aos agrotóxicos em cidade de intensa atividade do agronegócio e desfechos gestacionais adversos / Exposure to pesticides in a city with intense agribusinessactivity and adverse gestational outcomes / Exposición a plaguicidas en una ciudad con intensa actividad agroindustria y resultados gestacionales adversos

Objetivo: analisar a prevalência e os efeitos da exposição aos agrotóxicos sobre a ocorrência de desfechos gestacionais adversos. Método: estudo transversal de base populacional, constituído de 275 mulheres selecionadas a partir das áreas de cobertura das Estratégia da Saúde da Família, com idade igual ou maior que 18 anos. A coleta de dados ocorreu por meio da aplicação de um questionário estruturado, construído a partir da junção e adaptação de dois instrumentos validados, sendo um de condições de saúde autorreferida e um questionário de identificação do perfil de exposição familiar aos agrotóxicos. A análise de dados se deu por meio de análise bivariada, estratificada e regressão multivariada de Poisson. Resultados: houve uma incidência de aborto e natimortos de 20,73% na amostra, cujas variáveis associadas a estes desfechos de gravidez foram, contato atual com agrotóxicos, intoxicação prévia pelos agroquímicos e cor não branca, sendo observado a interação entre as mulheres que lavam roupas utilizadas na manipulação de agrotóxicos. Conclusão: há evidências de que a exposição materna a agrotóxicosse encontrapossivelmente associada a maior ocorrência de óbito fetal (aborto e natimorto).

Objective: to analyzethe prevalence and effects of exposure to pesticides on the occurrence of adverse pregnancy outcomes. Method: population-based cross-sectional study, consisting of 275 women selected from the areas covered by the Family Health Strategy, aged 18 years or older. Data collection took place through the application of a structured questionnaire, constructed from the combination and adaptation of two validated instruments, one of which is self-reported health conditions and a questionnaire to identify the profile of family exposure to pesticides. Data analysis was performed using bivariate and stratified analysis and multivariate Poisson regression. Results: there was an incidence of miscarriage and stillbirths of 20.73% in the sample, whose variables associated with these pregnancy outcomes were current contact with pesticides, previous intoxication by agrochemicals and non-white color, observing the interaction between women who wash clothes used in handling pesticides. Conclusion: there is evidence that maternal exposure to pesticides is possibly associated with a higher occurrence of fetal death (abortion and stillbirth).

Objetivo: analizar la prevalencia y los efectos de la exposición a plaguicidas en la ocurrencia de resultados adversos del embarazo. Método: estudio transversal de base poblacional, compuesto por 275 mujeres seleccionadas de las áreas de cobertura de la Estrategia Salud de la Familia, con edad igual o superior a 18 años. La recolección de datos se realizó mediante la aplicación de un cuestionario estructurado, construido a partir de la combinación y adaptación de dos instrumentos validados, uno de los cuales es el autoinforme de condiciones de salud y un cuestionario para identificar el perfil de exposición familiar a plaguicidas. El análisis de datos se realizó mediante análisis bivariado y estratificado y regresión de Poisson multivariada. Resultados: hubo una incidencia de abortos y mortinatos de 20,73% en la muestra, cuyas variables asociadas a estos desenlaces de embarazos fueron contacto actual con plaguicidas, intoxicaciones previas por agroquímicos y color no blanco, observándose la interacción entre mujeres que lavan ropa usada en manejo de pesticidas. Conclusión: existe evidencia de que la exposición materna a pesticidas posiblemente esté asociada con una mayor ocurrencia de muerte fetal (aborto y muerte fetal).

Gestational and Neonatal Outcomes in Cities in the Largest Coal Mining Region in Brazil.

Brazil has one of the largest mineral coal reserves in the world. More than 40% of this ore is in the Candiota Mine, in the extreme south of Brazil, which was previously identified as a hotspot of environmental pollution. In addition, an important part of Brazil's population suffers from socioeconomic vulnerability. Since there is no information on unfavorable gestational and neonatal outcomes associated with these problems, we conducted a cross-sectional study with 1950 mother-child binomials, aiming to evaluate the association between these outcomes and air pollution as well as socioeconomic, demographic and health variables in seven cities in the region. Of the total births, 11.6% were preterm and 9.5% of neonates had low birth weight (<2500 g). These conditions were also associated with skin color, previous abortions, birth type and prenatal care, as well as exposure to higher levels of coarse particulate matter (PM10) during the first trimester of pregnancy. Regarding air pollutants, although the daily limits for PM10 were exceeded on less than 5% of days, the annual average overtook the values proposed by WHO. Thus, we concluded that prematurity and low birth weight in this region are related to air pollution, and to socioeconomic variables and health care.

Intrauterine and Postnatal Exposure to High Levels of Fluoride Is Associated with Motor Impairments, Oxidative Stress, and Morphological Damage in the Cerebellum of Offspring Rats.

Fluoride (F) is abundantly present on Earth and plays a beneficial role in human health. However, exposure to high doses of F can be a risk, mainly in endemic fluorosis regions. In light of this, we investigated the effects of F exposure during the intrauterine and postnatal periods of rats, in doses similar to those recommended in drinking water and the levels of F in regions with endemic fluorosis, on the offspring rats' cerebellum. Pregnant rats were divided into three groups: control (received ultrapure water only), 10 mg F/L, and 50 mg F/L for a period of 42 days (21 days gestation and 21 days lactation). At the end of the lactation period, the male pups were evaluated by behavioral tests, morphological markers, and biochemistry assays. The results pointed out that 50 mg F/L exposure during the intrauterine and lactational period of rats is capable of promoting oxidative stress in the cerebellum with a decrease in Purkinje cell density and myelin basic protein compromise, which could be associated with functional motor impairments. In addition, although 10 mg F/L exposure promoted redox alterations, it did not affect other parameters evaluated, highlighting the safe use of F in low doses.

Sulfasalazine exposure during pregnancy and lactation induces alterations in reproductive behavior in adult female rat offspring.

AIMS: Sulfasalazine (SAS) is the first line drug in the treatment of chronic inflammatory bowel diseases in pregnant women. SAS and its metabolites cross the placenta and can be transferred through the milk. However, the long-term consequences to the reproductive system of offspring from dams exposed to SAS have not yet been studied. Thus, our study investigated the effects of SAS treatment during gestational and lactational periods on maternal care in F0 and reproductive outcomes in F1 females. MAIN METHODS: Wistar female rats (n = 10/group) received 300 mg/kg/day of SAS dissolved in carboxymethyl cellulose (CMC), by gavage, from gestational day 0 to lactation day 21 and 3 mg/kg/day of folic acid during gestation. The control group received CMC only. On PND 21, the female pups were selected for reproductive evaluation at different time points: infancy and adulthood. The reproductive parameters evaluated were installation of puberty (vaginal opening and first estrus), estrous cyclicity, reproductive organs weight, histological analysis of the ovary follicles and uterus, analysis of oxidative stress in ovarian tissue, reproductive behavior (sexual and maternal), and fertility. KEY FINDINGS: SAS treatment decreased the retrieving behavior in F0 females. The F1 females presented an increase in the lordosis score, frequency of lordosis of magnitude 3, and lipid peroxidation of ovarian tissues in both infancy and adult life. SIGNIFICANCE: The SAS effects observed in the current study represent a relevant concern for public health, as they demonstrated that treatment with SAS compromised the maternal motivation of dams and induced reproductive alterations in F1 females.

Tuberculosis congénita - el desafío parte con la madre / Congenital tuberculosis - the challenge starts with the mother

La tuberculosis es la enfermedad infecciosa por un solo agente que provoca más muertes en el mundo. A la fecha, no hay un registro de casos de embarazadas con tuberculosis en el mundo ni en Chile, y menos de los casos de tuberculosis congénita. El diagnóstico en ambas situaciones suele ser tardío y con malos resultados clínicos. Se presenta una revisión de la literatura con relación a tuberculosis perinatal y dos casos clínicos de los binomios madre e hijo afectados.

Tuberculosis is the single agent infectious disease that causes the most deaths in the world. To date, there is no record of pregnant women with tuberculosis in the world or in Chile, even less of congenital tuberculosis. Diagnosis in both situations is usually late and with poor clinical results. A literature review is presented in relation to perinatal tuberculosis and two clinical cases of affected mother and child binomials.

RUNX1 gene expression changes in the placentas of women smokers.

The placenta can be affected by environmental factors, such as exposure to cigarette smoke. This exposure in the fetal context is considered a risk factor for the development of short-term postnatal diseases, such as asthma. Asthma is an inflammatory disease characterized by predominant acquisition of CD4 T lymphocytes (TLs) of the Th2 type. Transcription factors such as GATA binding protein 3 (GATA3) and STAT6 actively participate in the differentiation of virgin TLs towards the Th2 profile, while transcription factors such as STAT1, T-Box transcription factor 21 (T-BET), RUNX1 and RUNX3 participate in their differentiation towards the Th1 profile. The objective of the current study was to evaluate the impact of exposure to cigarette smoke on the gene expression of STAT1, T-BET, GATA3, IL-4, RUNX1 and RUNX3 during the gestation period, and to determine whether the expression levels of these genes are associated with changes in global methylation. STAT1, GATA3, RUNX1 and RUNX3 protein and mRNA expression levels in the placental tissue of women smokers and non-smoking women were determined via immunohistochemistry and quantitative PCR (qPCR) respectively. Additionally, T-BET and IL-4 mRNA expression levels were determined by qPCR. On the other hand, global methylation was determined via ELISA. In the present study, significant increases were observed in RUNX1 transcription factor expression in placentas from women smokers when compared with placentas of non-smoking women. Similarly, significant increases in the expression of GATA3, IL-4 and RUNX3 mRNA were observed. The changes in gene expression were not associated with changes in the global methylation levels. Finally, a higher frequency of low-birth-weight infants were identified in cases of exposure to cigarette smoke during pregnancy when compared with infants not exposed to cigarette smoke during pregnancy. Thus, the data of the present study contributed to the understanding of the genetic and clinical impacts of exposure to cigarette smoke during pregnancy and its importance in maternal and fetal health.

Glyphosate Herbicide: Reproductive Outcomes and Multigenerational Effects.

Glyphosate base herbicides (GBHs) are the most widely applied pesticides in the world and are mainly used in association with GBH-tolerant crop varieties. Indiscriminate and negligent use of GBHs has promoted the emergence of glyphosate resistant weeds, and consequently the rise in the use of these herbicides. Glyphosate, the active ingredient of all GBHs, is combined with other chemicals known as co-formulants that enhance the herbicide action. Nowadays, the safety of glyphosate and its formulations remain to be a controversial issue, as evidence is not conclusive whether the adverse effects are caused by GBH or glyphosate, and little is known about the contribution of co-formulants to the toxicity of herbicides. Currently, alarmingly increased levels of glyphosate have been detected in different environmental matrixes and in foodstuff, becoming an issue of social concern. Some in vitro and in vivo studies have shown that glyphosate and its formulations exhibit estrogen-like properties, and growing evidence has indicated they may disrupt normal endocrine function, with adverse consequences for reproductive health. Moreover, multigenerational effects have been reported and epigenetic mechanisms have been proved to be involved in the alterations induced by the herbicide. In this review, we provide an overview of: i) the routes and levels of human exposure to GBHs, ii) the potential estrogenic effects of glyphosate and GBHs in cell culture and animal models, iii) their long-term effects on female fertility and mechanisms of action, and iv) the consequences on health of successive generations.

Association between Genetic Variants in NOS2 and TNF Genes with Congenital Zika Syndrome and Severe Microcephaly.

Zika virus (ZIKV) causes Congenital Zika Syndrome (CZS) in individuals exposed prenatally. Here, we investigated polymorphisms in VEGFA, PTGS2, NOS3, TNF, and NOS2 genes as risk factors to CZS. Forty children with CZS and forty-eight children who were in utero exposed to ZIKV infection, but born without congenital anomalies, were evaluated. Children with CZS were predominantly infected by ZIKV in the first trimester (p < 0.001) and had mothers with lower educational level (p < 0.001) and family income (p < 0.001). We found higher risk of CZS due the allele rs2297518[A] of NOS2 (OR = 2.28, CI 95% 1.17-4.50, p = 0.015). T allele and TT/CT genotypes of the TNF rs1799724 and haplotypes associated with higher expression of TNF were more prevalent in children with CZS and severe microcephaly (p = 0.029, p = 0.041 and p = 0.030, respectively). Our findings showed higher risk of CZS due ZIKV infection in the first trimester and suggested that polymorphisms in NOS2 and TNF genes affect the risk of CZS and severe microcephaly.