Reproductive technologies and Parkinson’s disease: experimental study of substantia nigra in the brain and motor functions on C57BL/6 and B6.CG-TG mice

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Abstract

Parkinson’s disease (PD) is an age-related neurodegenerative pathology characterized by abnormalities of the brain's dopaminergic system, alpha-synucleinopathy and motor dysfunction. Possible association of assisted reproductive technologies (ARTs) with neuropathologies is discussed in medicine literature, but there is a lack of experimental studies addressing this issue. The current study investigates the effects of ARTs, i.e. in vitro culture of preimplantation embryos and embryo transfer (ET) on the features characteristic for PD in offspring: motor dysfunction, decrease of neuronal density, e.g. density of dopaminergic neurons, as well as alpha-synuclein accumulation in substantia nigra pars compacta (SNpc). Male offspring of the B6.Cg-Tg strain and C57BL/6 strain (hereinafter referred as wild type, WT) obtained by ART (groups B6.Cg-Tg ET and WT ET) or by natural mating (groups B6.Cg-Tg CTL and WT CTL) were tested at the age of six months. Motor coordination and body balance were studied using the rotarod test; the density of neurons, as well as the accumulation of alpha-synuclein in the SNpc were assessed by immunohistochemical method. It was shown that B6.Cg-Tg mice obtained without ART (B6.Cg-Tg CTL) are characterized by the low density of neurons, including dopaminergic ones, as well as the accumulation of alpha-synuclein in SNpc as compared to wild type mice (WT CTL). Wild-type offspring obtained by ART (WT ET group) were characterized by the impairment in motor coordination and body balance, as well as by the decrease in the density of neurons in the SNpc, including dopaminergic ones. Offspring of the B6.Cg-Tg strain obtained by ART (B6.Cg-Tg ET group) were characterized by an increased accumulation of alpha-synuclein in the SNpc. The results of our study indicate possible association between using of modern reproductive technologies and predisposition to the neurodegenerative process and manifestations of the features characteristic to PD phenotype in offspring.

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About the authors

V. S. Kozeneva

Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University

Email: amstis@yandex.ru
Russian Federation, Novosibirsk; Novosibirsk

I. N. Rozhkova

Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences

Email: amstis@yandex.ru
Russian Federation, Novosibirsk

E. Y. Brusentsev

Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences

Email: amstis@yandex.ru
Russian Federation, Novosibirsk

T. A. Rakhmanova

Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University

Email: amstis@yandex.ru
Russian Federation, Novosibirsk; Novosibirsk

N. A. Shavshaeva

Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University

Email: amstis@yandex.ru
Russian Federation, Novosibirsk; Novosibirsk

S. G. Afanasova

Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University

Email: amstis@yandex.ru
Russian Federation, Novosibirsk; Novosibirsk

D. A. Lebedeva

Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences

Email: amstis@yandex.ru
Russian Federation, Novosibirsk

S. V. Okotrub

Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences

Email: amstis@yandex.ru
Russian Federation, Novosibirsk

T. N. Igonina

Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences

Email: amstis@yandex.ru
Russian Federation, Novosibirsk

S. Y. Amstislavskya

Institute of Cytology and Genetics Siberian Branch of the Russian Academy of Sciences

Author for correspondence.
Email: amstis@yandex.ru
Russian Federation, Novosibirsk

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2. Fig. 1. Experimental design. ART – assisted reproductive technologies; B6.Cg-Tg – transgenic model of Parkinson's disease; WT – wild type (C57BL/6); WT CTL group – C57BL/6 males born naturally: the number of animals taken for the study in the rotarod test n = 14, for brain assessment n = 9; B6.Cg-Tg CTL group – B6.Cg-Tg males born naturally: the number of animals taken for the study in the rotarod test and for brain assessment n = 9; WT ET group – C57BL/6 males born using ART: the number of animals taken for the study in the rotarod test and for brain assessment n = 4; Group B6.Cg-Tg ET – B6.Cg-Tg males born using ART: number of animals taken for the study in the rotarod test and for brain assessment n = 4.

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3. Fig. 2. Rotarod test. Latent time to animal fall. WT CTL – wild-type C57BL/6 offspring obtained by natural mating without assisted reproductive technologies (ART); B6.Cg-Tg CTL – B6.Cg-Tg offspring obtained without ART; WT ET – wild-type C57BL/6 offspring obtained with ART; B6.Cg-Tg ET – B6.Cg-Tg offspring obtained with ART. * p < 0.05 between WT ET and WT CTL; # p < 0.05 between B6.Cg-Tg ET and WT ET.

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4. Fig. 3. Density of neurons in the substantia nigra pars compacta (SNpc), neurons are labeled with antibodies against the neuronal marker (NeuN). (a) Number of neurons per mm3; (b) Schematic representation of the studied area in the brain. (c–f) Photomicrographs of sections in the substantia nigra pars compacta; (c) Wild-type C57BL/6 progeny obtained without the use of ART (WT CTL); (d) B6.Cg-Tg progeny obtained without the use of ART (B6.Cg-Tg CTL); (e) Wild-type C57BL/6 progeny obtained with the use of ART (WT ET); (f) B6.Cg-Tg progeny obtained with the use of ART (B6.Cg-Tg ET). Dotted lines indicate the borders of the substantia nigra. * p < 0.05 between B6.Cg-Tg CTL and WT CTL, and between WT ET and WT CTL; + p < 0.05 between B6.Cg-Tg ET and B6.Cg-Tg CTL; # p < 0.05 between B6.Cg-Tg ET and WT ET.

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5. Fig. 4. Density of dopaminergic neurons in the substantia nigra pars compacta (SNC), neurons labeled with antibodies against tyrosine hydroxylase (TH). (a) Number of neurons in mm3; (b) Schematic representation of the studied area in the brain. (c–f) Photomicrographs of sections in this area; (c) Wild-type C57BL/6 progeny obtained without ART (WT CTL); (d) B6.Cg-Tg progeny obtained without ART (B6.Cg-Tg CTL); (e) Wild-type C57BL/6 progeny obtained with ART (WT ET); (f) B6.Cg-Tg progeny obtained with ART (B6.Cg-Tg ET). * p < 0.05 between B6.Cg-Tg CTL and WT CTL, and between WT ET and WT CTL.

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6. Fig. 5. Density of neurons with alpha-synuclein in the substantia nigra pars compacta (SNC), neurons are labeled with antibodies against alpha-synuclein, neuronal nuclei are stained with DAPI; (a–d) – photomicrographs of sections in this region (entire SNpc; corresponding fragment); (a) – wild-type C57BL/6 progeny obtained without ART (WT CTL); (b) – B6.Cg-Tg progeny obtained without ART (B6.Cg-Tg CTL); (c) – wild-type C57BL/6 progeny obtained with ART (WT ET); (d) – B6.Cg-Tg progeny obtained with ART (B6.Cg-Tg ET); (e) – number of neurons in mm3. (f) – schematic designation of the studied region in the brain. Dotted lines indicate the boundaries of the substantia nigra. *** p < 0.001 between B6.Cg-Tg CTL and WT CTL; ++ p < 0.01 between B6.Cg-Tg ET and B6.Cg-Tg CTL; ### p < 0.001 between B6.Cg-Tg ET and WT ET.

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