The aryl hydrocarbon receptor mediates sex ratio distortion in the embryos sired by TCDD-exposed male mice.

Many reports describe an association between preconceptional paternal exposure to environmental chemicals, including the persistent organic pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with an increased number of female offspring. We chronically treated wild-type C57BL/6 male mice with TCDD to investigate a role for the aryl hydrocarbon receptor (AHR) transcription factor. These mice had a 14 % lower male:female sex ratio than control mice, which was not observed in TCDD-treated Ahr knock out mice. AHR target genes Cyp1a1 and Ahrr were upregulated in the liver and testis of WT mice and Ahr expression was higher in the epididymis (2-fold) and liver (18-fold) than in whole testis tissue. The AHR protein was localized to round spermatids, elongating spermatids, and Leydig cells in the testis of WT mice. These studies demonstrate AHR involvement in the sex ratio distortion of TCDD-exposed males and the need for evaluating the molecular and genetic mechanism of this process.

Exposição parental à pesticida e o risco de leucemia mieloide aguda na infância: uma revisão sistemática e metanálise / [Parental exposure to pesticides and the risk of acute myeloid leukemia in childhood: a systematic review and meta-analysis]

Introdução: As leucemias correspondem a 25-35% dos casos de câncer em menores de 15 anos. Dentre as leucemias da infância 15-20% à leucemia mieloide aguda (LMA). Estudos sugerem, que as leucemias agudas pediátricas têm origem na vida intra-uterina e que exposições a substâncias cancerígenas durante o período gestacional podem ser prejudiciais para o desenvolvimento fetal e contribui para a leucemogênese. As associações causais para a leucemia infantil ainda não estão bem estabelecidas. Metodologia: Foi realizada uma revisão sistemática e metanálise com o objetivo de compreender se a exposição ocupacional ou domiciliar parental à pesticida é um o risco para o desenvolvimento de LMA na infância A revisão foi elaborada conforme as recomendações da metodologia Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A busca foi realizada nas bases de dados eletrônicas PubMed, Scopus, Web of Science e Embase no período de agosto a setembro de 2018, resultando em 105 trabalhos. Após a remoção dos duplicados e a aplicação dos critérios de exclusão foram incluídos na revisão 8 estudos de caso-controle, observacional, longitudinal e retrospectivo publicados entre 1980 a 2018. Para a metanálise, os resultados binários de exposições foram coletados de acordo com o numero amostral de cada estudo, gerando tabelas de contingências para exposição à pesticidas com seus respectivos OR ou RR. Para o cálculo foi utilizado o software Rev manager version 5, especificando o efeito aleatórios baseado no método de Mantel-Haenszel. Resultado e Discussão: Apesar da conhecida teratogenicidade de diversos tipos de pesticidas, ao avaliar ensaios e estudos epidemiológicos esta correlação não fica tão clara. Isso se deve a complexidade e o número de variáveis que influem nesses resultados, neste estudo notou-se a influência significativa da exposição parental aos pesticidas no desenvolvimento da leucemia infantil, porem ao se avaliar apenas para LMA o resultado ainda não é conclusivo. Sugere-se que o baixo número de elementos (n) estatístico encontrado para LMA restringiu a potência estatística dos testes e também a alta variabilidade nas metodologias dos estudos avaliados. A primeira metanálise foi realizada com a relação da exposição aos pesticidas e desenvolvimento da LMA, com uma amostra com 240 casos e 643 controles, o OR combinado dos estudos foi de 1,33 (IC 95% = 0,91- 1,95) e p = 0,004. A segunda metanálise avaliou a influência da exposição parental a pesticidas e a chance de desenvolver leucemia, com amostra de 1586 casos e 4542 controles, o OR combinado dos estudos foi de 1.32 (IC 95% = 1.05 ­ 1.66), p = 0,02. Analisando a primeira metanálise concluímos que não pode-se afirmar que a exposição a pesticidas aumentam a chance de desenvolver LMA. Já na segunda metanálisa concluímos que houve uma associação entre a exposição parenteral a agentes pesticidas e o aumento de chances do desenvolvimento de leucemia na infância. Conclusão: Portanto podemos concluir que a exposição parental a pesticidas, sejam domésticos ou em ambiente laboral podem aumentar as chances da criança de desenvolver leucemia, porém quando relacionado ao subtipo LMA os dados ainda são inconclusivos.

Introduction: Leukemias account for 25-35% of cases of cancer in children under 15 years of age. Among childhood leukemias 15-20% to acute myeloid leukemia (AML). Studies suggest that acute pediatric leukemias originate in intrauterine life and that exposures to carcinogenic substances during the gestational period may be detrimental to fetal development and contribute to leukemogenesis. Causal associations for childhood leukemia are still not well established. Methods: A systematic review and meta-analysis was carried out to understand whether occupational or home exposure to the pesticide is a risk for the development of AML in childhood. The review was elaborated according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA). The search was performed in the electronic databases PubMed, Scopus, Web of Science and Embase from August to September 2018, resulting in 105 papers. After the removal of the duplicates and the application of the exclusion criteria, 8 case-control, observational, longitudinal and retrospective studies published between 1980 and 2018 were included in the review. For the meta-analysis, the binary results of exposures were collected according to the number sample of each study, generating contingency tables for exposure to pesticides with their respective OR or RR. The software Rev manager version 5 was used for the calculation, specifying the random effect based on the Mantel-Haenszel method. Results and Discussion: Despite the known teratogenicity of several types of pesticides, this correlation is not so clear when evaluating trials and epidemiological studies. This is due to the complexity and the number of variables influencing these results, in this study we noticed the significant influence of parental exposure to pesticides in the development of childhood leukemia, but when evaluating only for AML the result is not yet conclusive. It is suggested that the low number of statistical elements (n) found for AML restricted the statistical power of the tests and also the high variability in the methodologies of the studies evaluated. The first meta-analysis was performed with the relationship between exposure to pesticides and AML development, with a sample with 240 cases and 643 controls, the combined OR of the studies was 1.33 (95% CI = 0.91-1.95) ep = 0.004. The second meta-analysis evaluated the influence of parental exposure to pesticides and the chance of developing leukemia, with a sample of 1586 cases and 4542 controls, the combined OR of the studies was 1.32 (95% CI = 1.05 - 1.66), p = 0.02 . Analyzing the first meta-analysis we conclude that it can not be said that exposure to pesticides increases the chance of developing AML. In the second meta-analysis, we conclude that there was an association between parenteral exposure to pesticidal agents and an increased chance of developing childhood leukemia. Conclusion: Therefore we can conclude that parental exposure to pesticides, whether domestic or in the workplace, may increase the child's chances of developing leukemia, but when related to the AML subtype the data are still inconclusive.

Sexual differentiation and reproductive development of female rat offspring after paternal exposure to the anti-tumor pharmaceutical cisplatin.

Cisplatin (CP) is used to treat a number of cancers, including testicular cancer. Studies indicate that CP-treatment can impair spermatogenesis in humans and rodents by germ cell DNA binding, through different modes of action. CP-paternal exposure resulted in adverse effects in F1 male offspring. In this study, F1 female offspring was assessed for reproductive development after CP-paternal exposure. Peri-pubertal male rats, treated with 1mg/Kg/day of CP or vehicle for 3 weeks, were mated with unexposed females. F1 female offspring of CP-treated fathers showed a decrease in fetal ovary germ cells, in estrous cycle length and FSH levels, and an increase in the percentage of antral follicles in adults. Based on our previous results and the findings of the present work we concluded that CP-paternal exposure leads to adverse effects on rat male and female reproductive development, raising concern, in humans, for children born to men exposed to CP.