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Unexamined endocrine disruption: pesticides inhibit prostaglandin activity.

Androgens are widely recognized as important drivers of male sexual development in the fetus. (1) Some endocrine-disrupting chemicals have been shown to impact male sexual differentiation by affecting androgen production or blocking androgen receptors in target tissues. (2) Comparatively little attention has been paid to the role that ubiquitous biologically active lipids called prostaglandins play in these developmental processes, although studies have found that prostaglandins help initiate male genital development. (3,4,5) In this issue of EHP, researchers show that several structurally different endocrine-active pesticides suppress prostaglandin synthesis and signaling in mouse cells. (6)

"The research provides support for a new modality of endocrine disruption via prostaglandin inhibition," says senior study author Andreas Kortenkamp, a toxicologist at Brunel University in London. This study is thought to be the first to test pesticides for these effects.

Prostaglandins serve many purposes--from the promotion and resolution of the immune system's inflammatory response (7) to male sexual development in utero. (5) Previous studies have suggested that synthesis of prostaglandin-D2 (PGD2) may serve as a back-up mechanism for androgen-driven differentiation of Sertoli cells (8)--testicular cells that play an important role in the development and production of sperm.

A variety of mild analgesics (including acetaminophen, aspirin, and ibuprofen) have been shown to suppress PGD2 synthesis in human and rodent cell lines. (9) In one study, self-reported use of aspirin, acetaminophen, or ibuprofen during pregnancy was associated with cryptorchidism in some boys but not others, and experimental findings for rats indicated shorter anogenital distance with exposure to acetaminophen or aspirin. (10) According to the American Academy of Family Physicians, acetaminophen is generally considered safe for use during pregnancy, but this assessment is based on limited evidence. (11) Pregnant women are advised to use aspirin and ibuprofen only under a doctor's supervision. (11)

In the current study, Kortenkamp and colleagues tested the ability of 24 pesticides commonly used in the European Union to suppress PGD2 synthesis in juvenile mouse Sertoli cells. Fifteen of the pesticides, including imidacloprid, cypermethrin, and ortho-phenylphenol (OPP), inhibited PGD2 synthesis in a concentration-dependent manner. (6)

OPP, an antimicrobial agent used as a fungicide and sanitizer, was the most potent pesticide tested, suppressing PGD2 synthesis at a concentration of 175 nM. This made it nearly as potent as ibuprofen (used as a positive control), which suppressed PGD2 synthesis at a concentration of 128 nM. (6) "We were really surprised by the potency of some of these pesticides, namely OPP," Kortenkamp says.

Molecular modeling suggested that OPP and other pesticides may interfere with prostaglandins by inhibiting cyclooxygenase-1 and cyclooxygenase-2--the enzymes responsible for prostaglandin synthesis--in a manner similar to ibuprofen. Eleven of the 15 pesticides shown to suppress prostaglandin synthesis also acted as antiandrogens, chemicals that interfere with androgen production by blocking the androgen receptor. (6)

The new paper is important, because it shows that several of the investigated pesticides may obstruct both the androgen and prostaglandin signaling pathways, says David Kristensen, a toxicologist at the University of Copenhagen in Denmark. "The implications of this collective dual-hit scenario are not yet clear," says Kristensen, who was not involved in the current study.

It's difficult to predict likely effects of these pesticides on humans from cell culture studies alone, Kortenkamp says. The next step for his team is to identify priority chemicals for testing in animal models. Factors such as the rate at which a chemical enters the body and how rapidly it is metabolized and excreted can help to predict chemicals that would be expected to show activity in fetal tissue at experimental doses.

Lindsey Konkel is a New Jersey-based journalist who reports on science, health, and the environment.


(1.) Sharpe RM. Pathways of endocrine disruption during male sexual differentiation and masculinization. Best Pract Res Clin Endocrinol Metab 20(1):91-110 (2006), doi:10.1016/j.beem.2005.09.005.

(2.) Christiansen S, et al. Mixtures of endocrine disrupting contaminants modelled on human high end exposures: an exploratory study in rats. Int J Androl 35(3):303-316 (2012), doi:10.1111/j.13652605.2011.01242.x.

(3.) Gupta C, Goldman AS. The arachidonic acid cascade is involved in the masculinizing action of testosterone on embryonic external genitalia in mice. Proc Natl Acad Sci USA. 83(12):4346-4349 (1986), PMID:3086881.

(4.) Adams IR, McLaren A. Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis. Development 129(5): 1155-1164 (2002), PMID: 11874911.

(5.) Wilhelm D, et al. SOX9 regulates prostaglandin D synthase gene transcription in vivo to ensure testis development. J Biol Chem 282(14):10553-10560 (2007), doi:10.1074/jbc.M609578200.

(6.) Kugathas S, et al. Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse Sertoli cells, evidence of binding at the COX2 active site, and implications for endocrine disruption. Environ Health Perspect 124(3):452-459 (2016), doi:10.1289/ehp.1409544.

(7.) Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 31(5):986-1000 (2011), doi:10.1161/ATVBAHA.110.207449.

(8.) Koopman P. The delicate balance between male and female sex determining pathways: potential for disruption of early steps in sexual development. Int J Androl 33(2):252-258 (2010), doi:10.1111/j.1365-2605.2009.01001.x.

(9.) Kristensen DM, et al. Many putative endocrine disruptors inhibit prostaglandin synthesis. Environ Health Perspect 119(4):534-541 (2011), doi:10.1289/ehp.1002635.

(10.) Kristensen DM, et al. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Human Reprod 26(1):235-244 (2011), doi:10.1093/humanrep/deq323.

(11.) Servey J, Chang J. Over-the-counter medications in pregnancy. Am Fam Physician 90(8):548-555 (2014), PMID:25369643.

(12.) CDC. Biomonitoring Summary: ortho-Phenylphenol [website]. Atlanta, GA:U.S. Centers for Disease Control and Prevention (updated 4 December 2013). Available: Orthophenylphenol_BiomonitoringSummary.html [accessed 16 March 2016].

Caption: OPP is applied to citrus fruits and other crops after harvest to prevent spoilage. The general population is thought to consume levels of OPP well below recommended limits, although workers likely receive greater exposures. (12) It is unknown whether OPP causes human health effects. [c] David Thurber/Corbis


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Title Annotation:News: Science Selection
Author:Konkel, Lindsey
Publication:Environmental Health Perspectives
Article Type:Report
Geographic Code:1USA
Date:Apr 1, 2016
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