Embryo toxicity and teratogenicity of formaldehyde

C-14 formaldehyde crosses the placenta and enters fetal tissues. The incorp orated radioactivity is higher in fetal organs (i.e., brain and liver) than in maternal tissues. The incorporation mechanism has not been studied full y, but formaldehyde enters the single-carbon cycle and is incorporated as a methyl group into nucleic acids and proteins. Also, formaldehyde reacts ch emically with organic compounds (e.g., deoxyribonucleic acid, nucleosides, nucleotides, proteins, amino acids) by addition and condensation reactions, thus forming adducts and deoxyribonucleic acid-protein crosslinks. The fol lowing questions must be addressed: What adducts (e.g., N-methyl amino acid s) are formed in the blood following formaldehyde inhalation? What role do N-methyl-amino adducts play in alkylation of nuclear and mitochondrial deox yribonucleic acid, as well as mitochondrial peroxidation? The fact that the free formaldehyde pool in blood is not affected following exposure to the chemical does not mean that formaldehyde is not involved in altering cell a nd deoxyribonucleic acid characteristics beyond the nasal cavity. The terat ogenic effect of formaldehyde in the English literature has been sought, be ginning on the 6th day of pregnancy (i.e., rodents) (Saillenfait AM, et al. Food Chem Toxicol 1989, pp 545-48; Martin WJ. Reprod Toxicol 1990, pp 237- 39; Ulsamer AG, et al. Hazard Assessment of Chemicals; Academic Press, 1984 , pp 337-400; and U.S. Department of Health and Human Services. Toxicologic al Profile of Formaldehyde; ATSDR, 1999 [references 1-4., respectively, her ein]). The exposure regimen is critical and may account for the differences in outcomes. Pregnant rats were exposed (a) prior to mating, (b) during ma ting, (c) or during the entire gestation period. These regimens (a) increas ed embryo mortality; (b) increased fetal anomalies (i.e., cryptochordism an d aberrant ossification centers); (c) decreased concentrations of ascorbic acid; and (d) caused abnormalities in enzymes of mitochondria, lysosomes, a nd the endoplasmic reticulum. The alterations in enzymatic activity persist ed 4 mo following birth. In addition, formaldehyde caused metabolic acidosi s, which was augmented by iron deficiency. Furthermore, newborns exposed to formaldehyde in utero had abnormal performances in open-field tests. Dispa rities in teratogenic effects of toxic chemicals are not unusual. For examp le, chlorpyrifos has not produced teratogenic effects in rats when mothers are exposed on days 6-15 (Katakura Y, et al. Br J Ind Med 1993, pp 176-82 [ reference 5 herein]) of gestation (Breslin WJ, et al. Fund Appl Toxicol 199 6, pp 119-30; and Hanley TR, et al. Toxicol Sci 2000, pp 100-08 [references 6 and 7, respectively, herein]). However, either changing the endpoints fo r measurement or exposing neonates during periods of neurogenesis (days 1-1 4 following birth) and during subsequent developmental periods produced adv erse effects. These effects included neuroapoptosis, decreased deoxyribonuc leic acid and ribonucleic acid synthesis, abnormalities in adenylyl cyclase cascade, and neurobehavioral effects (Johnson DE, et al. Brain Res Bull 19 98, pp 143-47; Lassiter TL, et al. Toxicol Sci 1999, pp 92-100; Chakraborti TK, et al. Pharmacol Biochem Behav 1993, pp 219-24; Whitney KD, et al. Tox icol Appl Pharm 1995, pp 53-62; Chanda SM, et al. Pharmacol Biochem Behav 1 996, pp 771-76; Dam K, et al. Devel Brain Res 1998, pp 39-45; Campbell CG, et al. Brain Res Bull 1997, pp 179-89; and Xong X, et al. Toxicol Appl Phar m 1997, pp 158-74 [references 8-15, respectively, herein]). Furthermore, th e terata caused by thalidomide is a graphic human example in which the anim al model and timing of exposure were key factors (Parman T, et al. Natl Med 1999, pp 582-85; and Brenner CA, et al. Mol Human Repro 1998, pp 8 87-92 [references 16 and 17, respectively, herein]). Thus, it appears that more sensitive endpoints (e.g., enzyme activity, generation of reactive oxy gen species, timing of exposure) for the measurement of toxic effects of en vironmental agents on embryos, fetuses, and neonates are more coherent than are gross terata observations. The perinatal period from the end of organo genesis to the end of the neonatal period in humans approximates the 28th d ay of gestation to 4 wk postpartum. Therefore, researchers must investigate similar stages of development (e.g., neurogenesis occurs in the 3rd trimes ter in humans and neonatal days occur during days 1-14 in rats and mice, wh ereas guinea pigs behave more like humans). Finally, screening for teratoge nic events should also include exposure of females before mating or shortly following mating. Such a regimen is fruitful inasmuch as environmental age nts cause adverse effects on ovarian elements (e.g., thecal cells and ova [ nuclear-deoxyribonucleic acid and mitochondrial deoxyribonucleic acid]), as well as on zygotes and embryos before implantation. Mitochondrial deoxyrib onucleic acid mutations and deletions occur in human oocytes and embryos (P arman T, et al. Natl Med 1999, pp 582-85; and Brenner CA, et al. Mol Human Repro 1998, pp 887-92 [references 16 and 17, respectively, herein]). Thus, it is likely that xenobiotics directly affect n-deoxyribonucleic acid and/o r mitochondrial deoxyribonucleic acid in either the ovum or the zygote/embr yo or both (Thrasher JD. Arch Environ Health 2000, pp 292-94 [reference 18 herein]), and they could account for the increasing appearance of a variety of mitochondrial diseases, including autism (Lomard L. Med Hypotheses 1998 , pp 497-99; Wallace EC. Proc Natl Acad Sci 1994, pp 8730-46; and Giles RE, et al. Proc Natl Acad Sci 1980, pp 6715-19 [references 19-21, respectively , herein]). Two cases of human birth defects were reported in formaldehyde- contaminated homes (Woodbury MA, et al. Formaldehyde Toxicity 1983; pp 203- 11 [reference 22 herein]). One case was anencephalic at 2.76 ppm, and the o ther defect at 0.54 ppm was not characterized. Further observations on huma n birth defects are recommended.