Abstract
Thyroid hormones (THs) are essential for normal growth and development. Their role in skeletal and brain development is well established, with congenital hypothyroidism causing stunted growth and severe intellectual disability. THs are also important for the development of other tissues and organs, including the testis. Developmental hypothyroidism can manifest as smaller testes in early postnatal life that later develop into macroorchidism in adulthood due to increased proliferation of Sertoli cells. Effects of hypothyroidism on the testes can be modelled in rodents by exposing developing animals to TH-suppressing pharmaceuticals such as propylthiouracil (PTU) and methimazole (MMI). These drugs act by inhibiting the thyroperoxidase (TPO) enzyme in the thyroid gland, inhibiting the synthesis of THs. It is possible that environmental chemicals that inhibit TPO activity can also cause TH-mediated effects on the developing testis, but the extent to which this occurs is not known. Herein, we characterized the effects of perinatal exposure to the herbicide amitrole together with the antithyroid drug MMI. Pregnant Sprague-Dawley rats were exposed by oral gavage to two doses of amitrole (25 or 50 mg/kg body weight/day) or MMI (8 or 16 mg/kg body weight/day) from gestational day 7 until birth. After birth, pup exposure was continued by dosing lactating dams from day of delivery until pup day 16. Both chemicals caused a significant reduction in TH levels on day 16. This perinatal hypothyroidism disrupted both germ and Sertoli cell development, resulting in smaller testes and reduced seminiferous tubule diameter in 16-day old pups. Notably, fetal male blood progesterone levels were increased after exposure to both amitrole and MMI, whereas the amitrole-exposed animals also displayed increased estradiol levels. Our study raises concerns that exposure to environmental chemicals that happen to disrupt TH production may disrupt TH-dependent testis development, with adverse consequences to human reproductive health.
Original language | English |
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Article number | 125117 |
Journal | Environmental Pollution |
Volume | 363 |
Number of pages | 10 |
ISSN | 0269-7491 |
DOIs | |
Publication status | Published - 2024 |
Keywords
- Endocrine disrupting chemicals
- Thyroid
- Proliferation
- Hypothyroid
- Azole