The silent impact of pesticides: A systematic and critical review of endocrine disruption, FOXP2, and language development

Abstract

The rising global utilization of pesticides, organophosphates and pyrethroids, has elicited significant apprehensions regarding their possible effects on neurodevelopment, particularly in relation to language acquisition. Pesticides are acknowledged as endocrine-disrupting chemicals (EDCs); however, their precise impact on the hormonal regulation of FOXP2, a gene crucial for vocal learning and expressive language, has not been thoroughly investigated. This study seeks to systematically and critically analyze the correlation between pesticide exposure, testosterone levels, FOXP2 gene expression, and language-related outcomes, emphasizing sex-specific susceptibility. In accordance with PRISMA guidelines, 23 peer-reviewed empirical studies published from 2003 to 2024 were chosen from Scopus, PubMed, Web of Science, and ScienceDirect. A mixed-methods synthesis was executed across three domains: endocrine disruption, hormonal modulation of FOXP2, and behavioral-linguistic ramifications. The quality of the study was assessed with the ROBINS-I and SYRCLE tools, and the certainty of the evidence was assessed with a GRADE-style framework. The findings indicate that pesticide exposure is consistently linked to diminished testosterone levels, which subsequently downregulate FOXP2 expression in brain regions essential for speech. Changes in FOXP2 expression are linked to problems with expressive language and phonological errors in both humans and animals. The review differentiates between clinical impairments and subclinical variations, emphasizing limited yet significant sex-specific effects. These findings highlight the necessity for longitudinal, sex-sensitive research and enhanced public health policies to reduce developmental risks. Comprehending the impact of environmental toxins on language development is crucial for early intervention and the protection of neurocognitive outcomes.

Keywords

Language Development / Pesticide Exposure / Endocrine Disruption / Testosterone / FOXP2 Gene / Toxicology-Linguistics

CRediT authorship contribution statement

Azhari Azhari: Writing - original draft, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Muhammad Zikrullah: Writing - review & editing, Visualization, Validation, Methodology, Funding acquisition, Data curation. Ahmad Taufiq: Writing - review & editing, Supervision, Project administration, Methodology, Formal analysis, Data curation.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by Lembaga Pengelola Dana Pendidikan (LPDP/Indonesia Endowment Fund for Education) and Beasiswa Indonesia Bangkit (BIB), Ministry of Religion of the Republic of Indonesia Beasiswa.

Data availability

The data that has been used is confidential.

References

[1] Akhigbe T., Adeogun A., Hamed M., & Akhigbe R. (2023). Impact of organophosphate pesticide exposure on human semen quality and circulating testosterone: A systematic review and meta-analysis. Human Reproduction, 38(Supplement_1). https://doi.org/10.3389/fendo.2023.1227836

[2] Arnold A. P. (2009). The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Hormones and Behavior, 55(5), 570-578. https://doi.org/10.1016/j.yhbeh.2009.03.011

[3] Baron-Cohen S., Knickmeyer R. C., & Belmonte M. K. (2005). Sex differences in the brain: implications for explaining autism. Science, 310(5749), 819-823. https://doi.org/10.1126/science.1115455

[4] Bouchard M. F., Chevrier J., Harley K. G., Kogut K., Vedar M., Calderon N., Trujillo C., Johnson C., Bradman A., Barr D. B., & Eskenazi B. (2011). Prenatal exposure to organophosphate pesticides and IQ in 7-year-old children. Environmental Health Perspectives, 119(8), 1189-1195. https://doi.org/10.1289/ehp.1003185

[5] Bowers J. M., Perez-Pouchoulen M., Edwards N. S., & McCarthy M. M. (2013). Foxp2 mediates sex differences in ultrasonic vocalization by rat pups and directs order of maternal retrieval. The Journal of Neuroscience, 33(8), 3276-3283. https://doi.org/10.1523/JNEUROSCI.0425-12.2013

[6] Bowers J. M., Perez-Pouchoulen M., Roby C. R., Ryan T. E., & McCarthy M. M. (2014). Androgen modulation of Foxp1 and Foxp2 in the developing rat brain: Impact on sex specific vocalization. Endocrinology, 155(12), 4881-4894. https://doi.org/10.1210/en.2014-1486

[7] Chen P., Li Z., Li Y., Ahmad S. S., Kamal M. A., & Huo X. (2020). The language development via FOXP2 in autism spectrum disorder: A review. Current Pharmaceutical Design, 26(37), 4789-4795. https://doi.org/10.2174/1381612826666200909141108

[8] Costa L. G. (2006). Current issues in organophosphate toxicology. Clinica Chimica Acta, 366(1-2), 1-13. https://doi.org/10.1016/j.cca.2005.10.008

[9] Devanna P., Middelbeek J., & Vernes S. C. (2014). FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways. Frontiers in Cellular Neuroscience, 8. https://doi.org/10.3389/fncel.2014.00305

[10] Di Guardo F., Vloeberghs V., Bardhi E., Blockeel C., Verheyen G., Tournaye H., & Drakopoulos P. (2020). Low testosterone and semen parameters in Male partners of infertile couples undergoing IVF with a total sperm count greater than 5 million. Journal of Clinical Medicine, 9(12), 3824. https://doi.org/10.3390/jcm9123824

[11] Diamanti-Kandarakis E., Bourguignon J.-P., Giudice L. C., Hauser R., Prins G. S., Soto A. M., Zoeller R. T., & Gore A. C. (2009). Endocrine-disrupting chemicals: an endocrine society scientific statement. Endocrine Reviews, 30(4), 293-342. https://doi.org/10.1210/er.2009-0002

[12] Enard W., Gehre S., Hammerschmidt K., Hölter S. M., Blass T., Somel M., Brückner M. K., Schreiweis C., Winter C., Sohr R., Becker L., Wiebe V., Nickel B., Giger T., Müller U., Groszer M., Adler T., Aguilar A., Bolle I., & Pääbo S. (2009). A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice. Cell, 137 (5), 961-971. https://doi.org/10.1016/j.cell.2009.03.041

[13] Fisher S. E., & Scharff C. (2009). FOXP2 as a molecular window into speech and language. Trends in Genetics, 25(4), 166-177. https://doi.org/10.1016/j.tig.2009.03.002

[14] Gea M., Zhang C., Tota R., Gilardi G., Di Nardo G., & Schilir`o T. (2022). Assessment of five pesticides as endocrine-disrupting chemicals: Effects on estrogen receptors and aromatase. International Journal of Environmental Research and Public Health, 19 (4), 1959. https://doi.org/10.3390/ijerph19041959

[15] Giulioni C., Maurizi V., Castellani D., Scarcella S., Skrami E., Balercia G., & Galosi A. B. (2022). The environmental and occupational influence of pesticides on Male fertility: A systematic review of human studies. Andrology, 10(7), 1250-1271. https://doi.org/10.1111/andr.13228

[16] Haesler S., Rochefort C., Georgi B., Licznerski P., Osten P., & Scharff C. (2007). Incomplete and inaccurate vocal imitation after knockdown of FoxP2 in songbird basal ganglia nucleus area X. PLoS Biology, 5(12), Article e321. https://doi.org/10.1371/journal.pbio.0050321

[17] Haesler S., Wada K., Nshdejan A., Morrisey E. E., Lints T., Jarvis E. D., & Scharff C. (2004). FoxP2 expression in avian vocal learners and non-learners. The Journal of Neuroscience, 24(13), 3164-3175. https://doi.org/10.1523/JNEUROSCI.4369-03.2004

[18] Hamed M. A., Akhigbe T. M., Adeogun A. E., Adesoye O. B., & Akhigbe R. E. (2023). Impact of organophosphate pesticides exposure on human semen parameters and testosterone: A systematic review and meta-analysis. Frontiers in Endocrinology, 14. https://doi.org/10.3389/fendo.2023.1227836

[19] Hines M. (2011). Gender development and the human brain. Annual Review of Neuroscience, 34(1), 69-88. https://doi.org/10.1146/annurev-neuro-061010-113654

[20] Knapke E. T., Magalhaes D., de P., Dalvie M. A., Mandrioli D., & Perry M. J. (2022). Environmental and occupational pesticide exposure and human sperm parameters: A navigation guide review. Toxicology, 465, Article 153017. https://doi.org/10.1016/j.tox.2021.153017

[21] Kojima H., Katsura E., Takeuchi S., Niiyama K., & Kobayashi K. (2004). Screening for estrogen and androgen receptor activities in 200 pesticides by in vitro reporter gene assays using Chinese hamster ovary cells. Environmental Health Perspectives, 112(5), 524-531. https://doi.org/10.1289/ehp.6649

[22] Lahimer M., Capelle S., Lefranc E., Cabry R., Montjean D., Bach V., Ajina M., Ali H. Ben, Benkhalifa M., & Khorsi-Cauet H. (2023). Effect of pesticide exposure on human sperm characteristics, genome integrity, and methylation profile analysis. Environmental Science and Pollution Research, 30(31), 77560-77567. https://doi.org/10.1007/s11356-023-27695-7

[23] Liégeois F., Baldeweg T., Connelly A., Gadian D. G., Mishkin M., & Vargha-Khadem F. (2003). Language fMRI abnormalities associated with FOXP2 gene mutation. Nature Neuroscience, 6(11), 1230-1237. https://doi.org/10.1038/nn1138

[24] Manfo F. P. T., Moundipa P. F., Déchaud H., Tchana A. N., Nantia E. A., Zabot M., & Pugeat M. (2012). Effect of agropesticides use on male reproductive function: A study on farmers in djutitsa (Cameroon). Environmental Toxicology, 27(7), 423-432. https://doi.org/10.1002/tox.20656

[25] McCauley L. A., Anger W. K., Keifer M., Langley R., Robson M. G., & Rohlman D. (2006). Studying health outcomes in farmworker populations exposed to pesticides. Environmental Health Perspectives, 114(6), 953-960. https://doi.org/10.1289/ehp.8526

[26] Mnif W., Hassine A. I. H., Bouaziz A., Bartegi A., Thomas O., & Roig B. (2011). Effect of endocrine disruptor pesticides: A review. International Journal of Environmental Research and Public Health, 8(6), 2265-2303. https://doi.org/10.3390/ijerph8062265

[27] Mozzi A., Riva V., Forni D., Sironi M., Marino C., Molteni M., Riva S., Guerini F. R., Clerici M., Cagliani R., & Mascheretti S. (2017). A common genetic variant in FOXP2 is associated with language-based learning (dis)abilities: Evidence from two Italian independent samples. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 174(5), 578-586. https://doi.org/10.1002/ajmg.b.32546

[28] Peiris D. C., & Dhanushka T. (2017). Low doses of chlorpyrifos interfere with spermatogenesis of rats through reduction of sex hormones. Environmental Science and Pollution Research, 24(26), 20859-20867. https://doi.org/10.1007/s11356-017-9617-x

[29] Pérez-Herrera N., Polanco-Minaya H., Salazar-Arredondo E., Solís-Heredia M. J., Hernández-Ochoa I., Rojas-García E., Alvarado-Mejía J., Borja-Aburto V. H., & Quintanilla-Vega B. (2008). PON1Q192R genetic polymorphism modifies organophosphorous pesticide effects on semen quality and DNA integrity in agricultural workers from Southern Mexico. Toxicology and Applied Pharmacology, 230(2), 261-268. https://doi.org/10.1016/j.taap.2008.02.021

[30] Rauh V., Arunajadai S., Horton M., Perera F., Hoepner L., Barr D. B., & Whyatt R. (2011). Seven-year neurodevelopmental scores and prenatal exposure to chlorpyrifos, a common agricultural pesticide. Environmental Health Perspectives, 119 (8), 1196-1201. https://doi.org/10.1289/ehp.1003160

[31] Santos R., Piccoli C., Cremonese C., & Freire C. (2019). Thyroid and reproductive hormones in relation to pesticide use in an agricultural population in Southern Brazil. Environmental Research, 173, 221-231. https://doi.org/10.1016/j.envres.2019.03.050

[32] Siddique S., Farhat I., Kubwabo C., Chan P., Goodyer C. G., Robaire B., Chevrier J., & Hales B. F. (2022). Exposure of men living in the greater Montreal area to organophosphate esters: Association with hormonal balance and semen quality. Environment International, 166, Article 107402. https://doi.org/10.1016/j.envint.2022.107402

[33] Slotkin T. A. (2004). Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates. Toxicology and Applied Pharmacology, 198(2), 132-151. https://doi.org/10.1016/j.taap.2003.06.001

[34] Vernes S. C., Newbury D. F., Abrahams B. S., Winchester L., Nicod J., Groszer M., Alarcón M., Oliver P. L., Davies K. E., Geschwind D. H., Monaco A. P., & Fisher S. E. (2008). A functional genetic link between distinct developmental language disorders. New England Journal of Medicine, 359(22), 2337-2345. https://doi.org/10.1056/NEJMoa0802828

[35] Wołejko E., Łozowicka B., Jabłońska-Trypuć A., Pietruszyńska M., & Wydro U. (2022). Chlorpyrifos occurrence and toxicological risk assessment: A review. International Journal of Environmental Research and Public Health, 19(19), 12209. https://doi.org/10.3390/ijerph191912209

[36] Yu Z.-X., Zha X., & Xu X.-H. (2023). Estrogen-responsive neural circuits governing male and female mating behavior in mice. Current Opinion in Neurobiology, 81, Article 102749. https://doi.org/10.1016/j.conb.2023.102749