Advances in Molecular Oncology

Успехи молекулярной онкологии

2313-805X2413-3787

Publishing House ABV Press

820

10.17650/2313-805X-2025-12-3-116-131

RESEARCH ARTICLES

ЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИ

Molecular effects of the pesticides carbaryl, chlorpyrifos, mancozeb, thiram, and pendimethalin in conditionally normal cells in vitro: genotoxicity, clonogenicity and effects on the expression of genes associated with carcinogenesis

Молекулярные эффекты пестицидов карбарила, хлорпирифоса, манкоцеба, тирама и пендиметалина в условно-нормальных клетках in vitro: генотоксичность, клоногенность и влияние на экспрессию генов, ассоциированных с канцерогенезом

https://orcid.org/0000-0001-6388-1624

Lylova

E. S.

Лылова

Е. С.

Russian Federation

24 Kashirskoe Shosse, Moscow 115522, Russia

Россия, 115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-7301-605X

Popova

V. G.

Попова

В. Г.

Russian Federation

24 Kashirskoe Shosse, Moscow 115522, Russia

Россия, 115522 Москва, Каширское шоссе, 24

https://orcid.org/0009-0008-7714-114X

Zimin

K. А.

Зимин

К. А.

Russian Federation

24 Kashirskoe Shosse, Moscow 115522, Russia; Bld. 6, 1 Ostrovityanova St., Moscow 117513, Russia

Россия, 115522 Москва, Каширское шоссе, 24;Россия, 117513 Москва, ул. Островитянова, 1

https://orcid.org/0000-0002-0963-3432

Bukina

A. Yu.

Букина

А. Ю.

Russian Federation

24 Kashirskoe Shosse, Moscow 115522, Russia

Россия, 115522 Москва, Каширское шоссе, 24

https://orcid.org/0009-0001-2694-3387

Nurtdinova

V. A.

Нуртдинова

В. А.

Russian Federation

24 Kashirskoe Shosse, Moscow 115522, Russia

Россия, 115522 Москва, Каширское шоссе, 24

https://orcid.org/0009-0001-7152-7083

Shmakov

S. S.

Шмаков

С. С.

Russian Federation

27/1 Lomonosovsky Prospekt, Moscow 119192, Russia

Россия, 119991 Москва, Ленинские горы, 1, стр. 12

https://orcid.org/0000-0002-9710-8178

Yakubovskaya

M. G.

Якубовская

М. Г.

Russian Federation

24 Kashirskoe Shosse, Moscow 115522, Russia

Россия, 115522 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-8599-6833

Kirsanov

K. I.

Кирсанов

К. И.

Russian Federation

24 Kashirskoe Shosse, Moscow 115522, Russia; 6 Miklukho-Maklayа St., Moscow 117198, Russia

Россия, 115522 Москва, Каширское шоссе, 24; Россия, 117198 Москва, ул. Миклухо-Маклая, 6

https://orcid.org/0000-0003-0896-2952

Maksimova

V. P.

Максимова

В. П.

Russian Federation

Varvara Pavlovna Maksimova

24 Kashirskoe Shosse, Moscow 115522, Russia

Варвара Павловна Максимова

Россия, 115522 Москва, Каширское шоссе, 24

lavarvar@gmail.com

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России

Pirogov Russian National Research Medical University, Ministry of Health of RussiaФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России

Lomonosov Moscow State UniversityФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова»

Peoples’ Friendship University of RussiaФГАОУ ВО «Российский университет дружбы народов»

06102025

123

1161311110202511102025

2025

Lylova E.S., Popova V.G., Zimin K.А., Bukina A.Y., Nurtdinova V.A., Shmakov S.S., Yakubovskaya M.G., Kirsanov K.I., Maksimova V.P.

Лылова Е.С., Попова В.Г., Зимин К.А., Букина А.Ю., Нуртдинова В.А., Шмаков С.С., Якубовская М.Г., Кирсанов К.И., Максимова В.П.

https://creativecommons.org/licenses/by/4.0

https://umo.abvpress.ru/jour/article/view/820

Introduction. Cancer remains a major cause of mortality worldwide, with adverse environmental factors such as pesticides contributing significantly to its development. Despite the widespread use of various pesticides, the molecular mechanisms underlying their actions and carcinogenic potential have been studied for only a limited number of models, especially in normal human cells.Aim. To study the molecular effects of pesticides carbaryl, chlorpyrifos, mancozeb, thiram, and pendimethalin in nonmalignant HaCaT and MCF10A cells.Materials and methods. Non-toxic concentrations of pesticides were determined using the MTT assay. Genotoxicity was analyzed by the comet assay. Proliferative potential was assessed by clonogenic assay. Changes in the expression of genes associated with carcinogenesis were evaluated by real-time polymerase chain reaction.Results. Carbaryl caused DNA damage in MCF10A cells, promoted proliferation in both cell lines during clonogenic assay, as well as caused activation of biotransformation genes (AHR, GSTA4) in MCF10A cells, repression (CYP1B1, GSTA4) genes in HaCaT cells and lowered expression of inflammation genes (IL1a, IL1b, PTGES, IFNGR1). Chlorpyrifos did not have genotoxic effect and did not affect clonogenicity but caused induction of biotransformation (CYP1A1, CYP1B1), inflammation (IL1b, PTGES) genes, and genes BCL2 and DNMTs. Mancozeb and thiram did not show genotoxicity in HaCaT and MCF10A cells but activated individual repair genes (ATR/ATM). Thiram stimulated HaCaT cell proliferation in clonogenic assay, and mancozeb activated expression of proliferation regulation genes (CCND2, CCNE1, Ki-67) but did not affect colony growth; both fungicides decreased expression of inflammation genes (COX2, IL1a, IL1b). Pendimethalin caused DNA damage and activation of repair genes (ATR, GADD45a, PCNA) in both cell lines, as well as decreased expression of GLUT3 in HaCaT cells and induced expression of CYP1A1 in HaCaT cells and CYP1B1 in MCF10A cells.Conclusion. In this study, we performed a comprehensive assessment of the effects of pesticides on normal human cells. Our results indicate that pendimethalin, chlorpyrifos, and carbaryl exert the most procarcinogenic effect.

Введение. Злокачественные новообразования остаются одной из основных причин смертности в мире. В развитии данной патологии большую роль играет воздействие неблагоприятных факторов окружающей среды, в том числе пестицидов. Несмотря на широкий спектр используемых в сельском хозяйстве пестицидов, их молекулярные эффекты и канцерогенный потенциал изучены лишь в отношении небольшого числа моделей, включая нормальные клетки человека.Цель исследования – изучить молекулярные эффекты пестицидов карбарила, хлорпирифоса, манкоцеба, тирама и пендиметалина в условно-нормальных клетках HaCaT и MCF10A.Материалы и методы. Нетоксичные концентрации пестицидов определяли с помощью МТТ-теста. Генотоксичность анализировали методом ДНК-комет. Пролиферативный потенциал оценивали с помощью клоногенного анализа, изменение экспрессии генов, ассоциированных с канцерогенезом, – с использованием полимеразной цепной реакции в реальном времени.Результаты. Карбарил вызывал повреждение ДНК в клетках MCF10A, способствовал пролиферации клеток обеих линий в клоногенном тесте, а также приводил к активации генов биотрансформации (AHR, GSTA4) в клетках MCF10A, репрессии (CYP1B1, GSTA4) в клетках HaCaT и снижению экспрессии генов воспаления (IL1a, IL1b, PTGES, IFNGR1). Хлорпирифос не показал генотоксического эффекта и не влиял на клоногенность, но вызывал индукцию генов биотрансформации (CYP1A1, CYP1B1), воспаления (IL1b, PTGES) и генов BCL2 и DNMTs. Манкоцеб и тирам не проявляли генотоксичности в клетках HaCaT и MCF10A, но активировали отдельные гены репарации (ATR/ATM). Тирам стимулировал пролиферацию клеток HaCaT в клоногенном тесте, а манкоцеб активировал экспрессию генов – регуляторов пролиферации (CCND2, CCNE1, Ki-67), но не влиял на рост колоний; оба фунгицида снижали экспрессию генов воспаления (COX2, IL1a, IL1b). Пендиметалин вызывал повреждение ДНК и активацию экспрессии генов репарации (ATR, GADD45a, PCNA) в клетках обеих линий, а также снижал экспрессию GLUT3 в клетках HaCaT и индуцировал экспрессию генов CYP1A1 в клетках HaCaT и CYP1B1 – в клетках MCF10A.Заключение. В ходе комплексной оценки влияния пестицидов на нормальные человеческие клетки выявлено, что пендиметалин, хлорпирифос и карбарил оказывают наибольшее проканцерогенное действие.

pesticidecarcinogenesiscarbarylchlorpyrifosmancozebthirampendimethalin

пестицидканцерогенезкарбарилхлорпирифосманкоцебтирампендиметалин

The work was carried out with the financial support of the Russian Science Foundation (project No. 23-25-00541).

Работа выполнена при финансовой поддержке Российского научного фонда (проект № 23-25-00541)

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